Substituted amidinonaphthyl ester derivative

ABSTRACT

Substituted amidinonaphthyl ester compounds effective for treatment of thrombosis are represented by the following formula (I) and pharmaceutically acceptable acid addition salts thereof: ##STR1## wherein R 1  represents (4,5-dihydro-1H-imidazol-2-yl)amino group, (4,5-dihydro-1,3-thiazol-2-yl)amino group, amidino group, morpholinomethyl group, nitro group, amino group, dimethylamino group, ##STR2## R 3  represents hydrogen, methoxy group, hydroxyl group, acetylamino group, morpholino group, piperidino group, 1-pyrrolidinyl group or dimethylamino group, 
     m represents 0-4, 
     R 4  represents hydrogen or methyl group, 
     R 2  represents NH 2  CO(CH 2 ) n  --, 2-(carbamoyl)vinyl group or R 5  OOC(CH 2 ) n  --, 
     R 5  represents dimethylcarbamoylmethyl group, hydrogen or lower alkyl group, and 
     n represents 0-2.

This application has been filed under 35 USC 371 as a national stageapplication of PCT/JP95/02723 filed Dec. 27, 1995.

INDUSTRIAL FIELD OF THE INVENTION

The present invention relates to substituted amidinonaphthyl esterderivatives and pharmaceutical compositions containing the same as anactive ingredient. The present invention further relates tointermediates for producing the said derivatives.

PRIOR ART

A clot formed in the heart or blood vessels due to coagulation of bloodis called thrombus, and state of disease caused by the formation ofthrombus is called thrombosis. Thrombosis includes various diseases suchas cerebral infarction, myocardial infarction, pulmonary infarction andthe like.

The methods for treatment of thrombosis is roughly classified into twomethods from the point of action. That is, one is anti-thrombotic methodwhich inhibits formation of thrombus and another is thrombolysis methodaccording to which the formed thrombi are resolved.

It is considered that according to the thrombolysis method, plasminogenwhich is a precursor of fibrinolysis regulatory factor is activated intoplasmin by giving a thrombolysis and this plasmin decomposes fibrinwhich forms thrombi in blood vessel whereby thrombi are resolved to openoccluded parts. Medicines used for the thrombolysis method include, forexample, tissue plasminogen activators (t-PA) which are plasminogenactivators activating plasminogen into plasmin, substances in livingbody such as urokinase (UK) and the like, substances produced by cellssuch as staphylokinase, streptokinase and the like, and recombinantsthereof.

Problems to be Solved by the Invention

However, the above t-PA and others are generally considered to beeffective when intravenously administered. Since they are short inhalf-life in blood and rapidly removed from liver and, furthermore,inhibitors are present in living bodies, they must be administered in alarge dosage to develop the thrombolysis action at the part wherethrombi have been produced. The high dosage of the thrombus resolventgiven in a short time is expected to markedly enhance thethrombus-resolving action systemically and open the occluded parts, and,on the other hand, it has been reported that it causes serious bleeding.Moreover, it has been reported as a result of animal experiments andclinical trials that even if the occluded parts are temporarily openedby the administration of the thrombolytic agents, the parts are apt tobe reoccluded. This is a serious problem. Another problem inadministration is that since the thrombolytic agents are injections, ifthey are administered for a long period of time, it gives a heavy burdento patients.

For the above reasons, development of medicines which have thrombolyticactivity action and can be orally administered has been desired toreduce the burden for patients.

Means for Solving the Problems

The inventors have found that compounds represented by the followingformula (I) have fibrinolysis promoting action and excellentthrombolysis action. As a result, the above problems have been solvedand the present invention has been accomplished. That is, the presentinvention relates to a compound represented by the formula (I): ##STR3##(wherein R₁ represents (4,5-dihydro-1H-imidazol-2-yl)amino group,(4,5-dihydro-1,3-thiazol-2-yl)amino group, amidino group,morpholinomethyl group, nitro group, amino group, dimethylamino group,##STR4## R₃ represents hydrogen, methoxy group, hydroxyl group,acetylamino group, morpholino group, piperidino group, 1-pyrrolidinylgroup or dimethylamino group,

m represents 0-4,

R₄ represents hydrogen or methyl group,

R₂ represents NH₂ CO(CH₂)_(n) --, 2-(carbamoyl)vinyl group or R₅OOC(CH₂)_(n) --,

R₅ represents dimethylcarbamoylmethyl group, hydrogen or lower alkylgroup, and

n represents 0-2).

The present invention further relates to pharmaceutical compositionscontaining the above compound (I).

Furthermore, the present invention relates to a compound represented bythe formula (II) useful as an intermediate for the production of thecompound (I): ##STR5## (wherein R₂ represents NH₂ CO(CH₂)_(n) --,2-(carbamoyl)vinyl group or R₅ OOC(CH₂)_(n) --,

R₅ represents dimethylcarbamoylmethyl group, hydrogen or lower alkylgroup, and

n represents 0-2, with a proviso that R₅ =CH₃ and n=0 are excluded).

The present compound (1) has fibrinolysis promoting action and exhibitsexcellent thrombusresolving action and is effective for treatment ofdiseases caused by thrombus. That is, it can be used as medicines forgeneral thrombosis and embolism, for example, medicines for treatment ofthrombosis and embolism such as venous thrombosis, myocardialinfarction, pulmonary occlusion, cerebral embolism, slowly advancingcerebral thrombosis, and thrombosis and embolism caused by operation ofblood vessels and extracorporeal circulation, and improvement ofobstruction of blood stream, improvement of various diseases caused bychronic artery occlusion, and treatment of thrombosis and embolismcaused by ischemic cerebral artery injuries.

Representative processes for producing the present compound (I) andintermediate therefor are shown below.

Process for producing substituted amidinonaphthyl ester derivatives:##STR6## (wherein R₁ and R₂ are as defined above).

The present compound (I) can be produced by reacting a carboxylic acidderivative represented by the formula (III) or a reactive intermediatethereof with a substituted amidinonaphthol derivative represented by theformula (II) in the above Scheme A.

The reactive intermediate here means a reaction intermediate obtained bythe reaction of the carboxylic acid derivative (III) with an acid halide(IV) used for general dehydration condensation, a mixed acid anhydride,N,N'-dicyclohexylcarbodiimide (DCC),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC),diphenylphosphorylazide (DPPA) or the like which is generally used as adehydration condensation agent.

The process for producing the present compound (I) will be explained inmore detail.

The carboxylic acid derivative (III) is dissolved or suspended in anorganic solvent such as N,N-dimethylformamide (DMF),N,N-dimethylacetamide (DMA), pyridine, a mixture thereof, or the likeand is reacted with a carboxylic acid activator such as DCC, EDC, DPPAor the like. Then, the substituted aminodinaphthol derivative (II) isadded, whereby the present compound (I) can be produced.

For example, when DCC is used as a dehydration condensation agent, thecarboxylic acid derivative (III) is dissolved or suspended in a suitablesolvent such as anhydrous or hydrous pyridine or the like, and thesubstituted amidinonaphthol derivative (II) is added thereto, followedby stirring under cooling or heating. After completion of the reaction,dicyclohexylurea (DCU) in the reaction mixture is removed, followed bycarrying out usual treatments, whereby the present compound (I) can beproduced. If necessary, the product is further purified by silica gelcolumn chromatography.

When acid halide (IV) is used, the carboxylic acid derivative (III) isreacted with an acid halogenating agent such as thionyl chloride,thionyl bromide, phosphorus pentachloride or the like to obtain an acidhalide derivative. Thereto is added the substituted amidinonaphtholderivative (II), whereby the present compound (I) can be produced. Asthe reaction solvent, DMF, DMA, dimethyl sulfoxide (DMSO), pyridine orthe like is used and the reaction is effected using adehydrohalogenating agent under cooling or heating. As thedehydrohalogenating agent, can be used inorganic bases such as potassiumcarbonate, sodium carbonate, sodium hydroxide and the like and organicbases such as triethylamine, pyridine, dimethylaniline and the like.

When the terminal functional group of R₂ is a carboxylic acid, thecorresponding amide or lower alkyl ester is treated with an inorganicacid such as hydrochloric acid, sulfuric acid or the like or an organicacid such as methanesulfonic acid, ethanesulfonic acid or the like underheating, whereby the present compound (I) can be produced.

The thus obtained present compound (I) can be converted to thecorresponding acid addition salt by usual salt exchanging method. Anyacids can be used as far as the salts are usable as medicines, andexamples of the acids are inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid and the like andorganic acids such as acetic acid, lactic acid, citric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,succinic acid, fumaric acid, maleic acid and the like.

Process for the production of substituted amidinonaphthol derivative:

Substituted amidinonaphthol derivative (II) is a compound useful as anintermediate for producing the present compound (I). ##STR7##

The substituted amidinonaphthol derivative (II) can be produced byvarious synthesis reactions as shown in Scheme B using known compounds(1), (2), (3) and (4) as starting materials. That is, ester (8) can beproduced by esterification of compounds (3) and (4) using various loweralcohols or halogenated alkyls or bromination of compound (7).

Lactone compound (10) can be produced by the process of A. F. Hardman etal (J. Am. Chem. Soc., 70, 2119(1984)) from compound (1) throughcyanoethyl compound (5) and carboxylic acid compound (9).

Nitrile (11)-R_(2a) can be produced by reacting copper cyanide withcompounds (8) and (10) in accordance with the process of Friedman et al(J. Org. Chem., 26, 2522(1961)). Nitrile (11)-R2b can be produced byformylating compound (2) using paraformaldehyde or the like to yieldcompound (6) and subjecting the compound (6) to the Wittig reactionusing phospholan.

Substituted amidinonaphthol derivative (II) can be produced throughimidate (12) in accordance with the Pinner process. The imidate (12) isproduced by reacting the nitrile (11) with an equal or much excessamount of a lower alcohol in the presence of a hydrogen halide such ashydrogen chloride or hydrogen bromide under cooling or heating, and theimidate is further reacted with ammonia in a solvent such as a loweralcohol, N,N-dimethylformamide, dimethyl sulfoxide or the like undercooling or heating, whereby the substituted amidinonaphthol derivative(II) can be produced.

The present compound can be administered to mammals (including humanpatients) in the form of oral dosage or rectal dosage in view of itspharmacological action.

Furthermore, the present compound can be administered as one medicine ormixtures with other medicines. They can be administered as singlecompound or compounds, but are generally administered in the form ofpharmaceutical composition. Examples of the composition are tablet,powder, capsule, syrup, and aqueous solution. For the oral compositions,there may be used ordinary additives such as excipient, lubricant,disintegrator, wetting agent and the like. Oral liquid formulation maybe in the form of aqueous or oil suspension, solution, emulsion, syrup,elixir or the like, or it may be used as a dry syrup which is repreparedwith water or other appropriate solvents before use. The liquidformulation can contain usual additives such as suspending agent,perfume, diluent and emulsifying agent.

In the case of rectal administration, the composition can beadministered as a suppository. The suppository is prepared usingappropriate bases such as cacao butter, laurin butter, Macrogol, glycerogelatin, Witepsol, sodium stearate or mixtures thereof and, ifnecessary, with addition of emulsifying agent, suspending agent,preservative and the like.

Examples of the excipient and others used in the compositions areenumerated below.

Excipient: Calcium hydrogenphosphate, synthetic aluminum silicate,magnesium metasilicate aluminate, aluminum-magnesium hydroxide,magnesium silicate, calcium carbonate, magnesium carbonate, calciumhydrogenphosphate, precipitated silicic acid anhydride, silicic acidanhydride, Avicel, various starches, dextrin, carboxymethyl starch(CMS), lactose.

Binder: Ethylcellulose (EC), sodium carboxymethylcellulose (CMC-Na),low-substitution hydroxypropylcellulose (L-HPC),hydroxypropylmethylcellulose (HPMC), methylcellulose (MC),hydroxypropylcellulose (HPC), various starches, dextrin, sodiumalginate, gelatin, polyvinyl alcohol (PVA), polyvinyl pyrrolidone (PVP).

Disintegrator: Synthetic aluminum silicate, magnesium metasilicatealuminate, CMC-Ca, CMC, Avicel, L-HPC, HPMC, MC, various starches, CMS,hydroxypropyl starch (CPS).

Solidification inhibitor: Precipitated silicic acid anhydride, syntheticaluminum silicate.

Lubricant: Synthetic aluminum silicate, silicic acid anhydride, talc,Avicel.

Corrigent: Mannitol, citric acid, sodium citrate, sugar.

Emulsifying agent: Gelatin, citric acid, sodium citrate, polyoxyethylenehardened castor oil, Macrogol (PEG), propylene glycol fatty acid esters,polyoxyethylenepolyoxypropylene glycol, propylene glycol, sodiumlaurylsulfate, phospholipid.

Stabilizing agent: Sodium hydrogensulfite, polyoxyethylene hardenedcastor oil, PEG, propylene glycol fatty acid esters,polyoxyethylenepolyoxypropylene glycol, propylene glycol, sodiumlaurylsulfate, various natural and synthetic cyclodextrins,phospholipid.

Absorption promotor: Polyoxyethylene hardened castor oil, PEG, propyleneglycol fatty acid esters, polyoxyethylenepolyoxypropylene glycol,propylene glycol, sodium laurylsulfate, various natural and syntheticcyclodextrins, middle-chain fatty acid triglycerides.

Solubilizing agent: Ethanol, polyoxyethylene hardened castor oil, PEG,propylene glycol fatty acid esters, polyoxyethylenepolyoxypropyleneglycol, propylene glycol, sodium laurylsulfate, various natural andsynthetic cyclodextrins.

Suspending agent: CMC-Na, HPMC, MC, HPC, sodium alginate, gelatin,propylene glycol, sodium laurylsulfate.

Coating agent: EC, magnesium silicate, talc, titanium oxide, calciumcarbonate, triacetin, carboxymethylethylcellulose (CMEC), celluloseacetate phthalate (CAP), HPMC, hydroxypropylmethylcellulose phthalate(HPMCP), MC, HPC, sodium alginate, polyvinyl acetal diethylaminoacetate,sodium polyacrylate, copolymers of various acrylic acid and methacrylicacid derivatives, sodium polyglycolate.

Coloring agent: Titanium oxide, tar dye, caramel.

Dosage of the present compound when orally administered to human is100-1000 mg/day, preferably 300-900 mg/day, more preferably 400-800mg/day. However, when it is administered to human for curative purpose,the dosage is suitably adjusted depending on degree of seriousness ofdisease, age, body weight and the like.

The present invention will be explained more specifically by thefollowing examples and formulation examples, which never limit theinvention.

EXAMPLE 1

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoate.dihydrochloride:

45 Milliliters of 20% hydrous pyridine was added to 2.85 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.hydrochloride, 3 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g ofN,N'-dicyclohexylcarbodiimide (hereinafter referred to as "DCC") and 131mg of 4-dimethylaminopyridine (hereinafter referred to as "DMAP"),followed by stirring for 2 hours under cooling with ice and 3 days undercooling with water. The precipitate was filtered and the filtrate wasconcentrated under reduced pressure. To the residue was added 15 ml ofN,N-dimethylformamide (hereinafter referred to as "DMF"), and a smallamount of the insoluble matter was filtered off. The filtrate was addeddropwise to 500 ml of a mixed liquid of ether and acetone (10:1) andthis was stirred for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product.

Then, the product was subjected to silica gel column chromatographyusing methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, andthe desired fractions were collected and the solvent was distilled offunder reduced pressure. The residue was dissolved in 10 ml of methanoland 3.6 ml of 6N hydrochloric acid, and the solution was added dropwiseto 400 ml of a mixed liquid of ether and acetone (3:1) under coolingwith ice. After stirring for 3 hours, the precipitate was collected byfiltration to obtain 963 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.74  (1H, S)      7.64      (1H, d, J = 8.9 Hz)    9.72   (2H, S)      7.54      (2H, d, J = 8.9 Hz)    9.52   (2H, S)      7.03      (1H, S)    8.80   (2H, S)      3.99      (2H, S)    8.67   (1H, S)      3.73      (4H, S)    8.31   (1H, d, J = 8.9 Hz)                        8.22      (2H, d, J = 8.6 Hz)    8.09   (1H, d, J = 9.2 Hz)                        7.96      (1H, d, J = 8.9 Hz)    7.73   (1H, S)    ______________________________________

Reference Example 1

Preparation of methyl 2-hydroxy-6-bromo-1-naphthylacetate:

126.5 Grams of 2-hydroxy-6-bromo-1-naphthylacetic acid, 700 ml ofmethanol and 2 ml of concentrated sulfuric acid were stirred at roomtemperature for 24 hours. Then, the reaction mixture was concentratedunder reduced pressure. The precipitate was collected by filtration andwashed with small amounts of methanol and water to obtain 125.5 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.01     (1H, S) 6.93-8.36     (5H, m)    4.04      (2H, S) 3.59          (3H, S)    ______________________________________

Reference Example 2

Preparation of 2-hydroxy-6-cyano-1-naphthylacetic acid:

100 Milliliters of DMF was added to 177 g of methyl2-hydroxy-6-bromo-1-naphthylacetate and 70.9 g of cuprous cyanide, andrefluxed under heating for 3.5 hours in a nitrogen stream. With stirringunder heating, 300 ml of water was added and supernatant liquid wasdecanted, and then this procedure was repeated. To the resulting residuewas added 2.3 liters of a 4% aqueous sodium hydroxide solution, followedby stirring at 25° C. for 1 hour. The insoluble matter was filtered, andconcentrated hydrochloric acid was added to the filtrate and theprecipitate was collected by filtration. To this collected precipitatewas added 200 ml of water, and thereto were added 501 g of ferroussulfate.heptahydrate and 60 ml of concentrated hydrochloric acid,followed by stirring at 70° C. for 1 hour. After leaving for cooling,the resulting precipitate was collected by filtration and sufficientlywashed with water. Thereafter, 3 liters of methanol was added thereto todissolve the precipitate at 40° C. The insoluble matter was filteredoff, and 3 liters of water was added to the filtrate to obtain a crudeproduct. The product was repeatedly subjected to recrystallization with10% hydrous methanol to obtain 42 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    12.23       (1H, br)                        10.50       (1H, br)    7.03-8.82   (5H, m) 3.99        (2H, S)    ______________________________________

Reference Example 3

Preparation of methyl 2-hydroxy-6-cyano-1-naphthylacetate:

A solution containing 18.2 g of 2-hydroxy-6-cyano-1-naphthylacetic acid,250 ml of methanol and 3 g of methanesulfonic acid was stirred at 40° C.to perform dissolution, followed by stirring at room temperature for 2days. Then, 5 g of active carbon was added, followed by stirring for 30minutes. Thereafter, the insoluble matter was filtered off and thesolvent was distilled off under reduced pressure. To the residue wasadded 50 ml of 50% hydrous methanol, and then the precipitate wascollected by filtration to obtain 13 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.49     (1H, S) 8.41       (1H, S)    7.49-8.22 (3H, m) 7.34       (1H, d, J = 8.8 Hz)    4.08      (2H, S) 3.61       (3H, S)    ______________________________________

EXAMPLE 2

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride:

1.2 Liter of anhydrous methanol was added to 58 g of methyl2-hydroxy-6-cyano-1-naphthylacetate, and the solution was saturated withhydrogen chloride gas under cooling with ice, followed by stirring at50° C. for 24 hours. The precipitate was collected by filtration andwashed with a small amount of ether. To the collected precipitate wasadded 3.1 liters of anhydrous methanol, and ammonia gas was passedtherethrough under cooling with water and stirring to dissolve theprecipitate, followed by stirring for 4 days at the same temperature.The precipitate was collected by filtration and washed with a smallamount of methanol. To this collected precipitate was added 730 ml ofwater, and 240 ml of concentrated hydrochloric acid was added undercooling with ice, followed by stirring for 30 minutes. Then, theprecipitate was collected by filtration and washed with 250 ml ofacetone to obtain 44.2 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.63       (1H, S) 3.90         (2H, S)    8.84-10.15  (4H, br)                        6.48-8.81    (7H, m)    ______________________________________

EXAMPLE 3

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-acetylaminoethyl)iminomethylaminomethylamino!benzoate.dihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 1.4 g of 4-(2-acetylaminoethyl)iminomethylaminomethylamino!benzoicacid.hydrobromide, 1.0 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 884 mg of DCC and43.6 mg of DMAP, followed by stirring for 2 hours under cooling with iceand 4 days at room temperature. The precipitate was filtered and thefiltrate was added dropwise to 250 ml of a mixed liquid of ether andacetone (1:10) and this was stirred for 24 hours under cooling with ice.Then, the precipitate was collected by filtration. To this collectedprecipitate was added 7 ml of DMF to dissolve the precipitate withheating, and 1.46 ml of concentrated hydrochloric acid was added undercooling with ice and stirring. This solution was added dropwise to 400ml of ether.acetone (1:20), followed by stirring for 1 hour undercooling with ice and then 24 hours under cooling with water. After thesupernatant was decanted, 20 ml of DMF was again added to the residue todissolve the residue with heating, and further 1.5 ml of concentratedhydrochloric acid was added under cooling with water and stirring. Thissolution was added dropwise to 400 ml of acetone, followed by stirringfor 1 hour under cooling with ice and then 24 hours under cooling withwater. Thereafter, the precipitate was collected by filtration to obtaina crude product.

Then, the product was subjected to silica gel column chromatographyusing a mixed liquid of methyl ethyl ketone-water-acetic acid (80:15:5)as an eluent, and the desired fractions were collected and the solventwas distilled off under reduced pressure. The residue was dissolved in 8ml of DMF and 1 ml of concentrated hydrochloric acid, and the solutionwas added dropwise to 200 ml of acetone under cooling with ice. Afterstirring for 1 hour under cooling with ice and then 24 hours undercooling with water, the precipitate was collected by filtration toobtain 939.2 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.44  (1H, S)       7.78      (1H, S)    9.75   (2H, S)       7.71      (1H, d, J = 8.9 Hz)    9.53   (2H, S)       7.60      (2H, d, J = 8.9 Hz)    8.73   (1H, S)       7.12      (1H, S)    8.46   (2-3H, br)    4.06      (2H, S)    8.38   (1H, d, J = 8.9 Hz)                         3.52      (2H, brs)    8.28   (2H, d, J = 8.9 Hz)                         3.25-3.47 (2H, m)    8.18   (1H, d, J = 9.2 Hz)                         3.00      (3H, S)    7.94-8.14           (2H, m)       1.99      (3H, S)    ______________________________________

Reference Example 4

Preparation of 2-hydroxy-6-bromo-1-(2-cyanoethyl)naphthalene:

To 44.8 g of 6-bromo-2-naphthol were added 120 ml of toluene and 8.8 gof sodium hydroxide, followed by stirring at 65° C. for 30 minutes.Then, thereto was added dropwise 11.4 g of acrylonitrile at 80° C.,followed by stirring at the same temperature for 3.5 hours. After leftfor cooling, the toluene layer was decanted, and to the residue wasadded 240 ml of water. A small amount of insoluble matter was filteredoff, and to the filtrate was added 140 ml of 5% hydrochloric acid. Theprecipitate was collected by filtration and sufficiently washed withwater. The resulting crude product was recrystallized from ethanol toobtain 30.7 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.05      (1H, S) 7.03-8.26     (5H, m)    2.33-3.62  (4H, m)    ______________________________________

Reference Example 5

Preparation of 3-(2-hydroxy-6-bromo-1-naphthyl)propionic acid:

To 27.6 g of 2-hydroxy-6-bromo-1-(2-cyanoethyl)naphthalene was added 88g of 10% sodium hydroxide, followed by refluxing for 7 hours underheating. After the mixture was left for cooling, it was made acidic withdilute hydrochloric acid, and then the precipitate was collected byfiltration and washed with water. To the collected precipitate was added1.2 liter of water, and furthermore 168 g of sodium hydrogencarbonatewas added with stirring to dissolve the precipitate. Then, a smallamount of insoluble matter was filtered off, and concentratedhydrochloric acid was added to the filtrate to render the filtrateacidic. Then, the precipitate was collected by filtration and washedwith water to obtain 17.3 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.86-11.66  (2H, brs)                         6.71-8.28   (5H, m)    2.08-3.44   (4H, m)    ______________________________________

Reference Example 6

Preparation of 4-bromobenzo 1,2-f!-3,4-dihydrocoumarin:

30 Milliliters of toluene was added to 5.9 g of3-(2-hydroxy-6-bromo-1-naphthyl)propionic acid, followed by refluxingwith heating for 5.5 hours. After the mixture was left for cooling, 20ml of cyclohexane was added, followed by stirring for 30 minutes, andthereafter the precipitate was collected by filtration to obtain 5.1 gof the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    7.04-8.44 (5H, m)                   2.64-3.65 (4H, m)    ______________________________________

Reference Example 7

Preparation of methyl 3-(2-hydroxy-6-cyano-1-naphthyl)propionate:

To 83.1 g of 4-bromobanzo 1,2-f!-3,4-dihydrocoumarin were added 200 mlof DMF and 33.1 g of cuprous cyanide, and the mixture was stirred at140°-145° C. for 7 hours in a nitrogen stream. After left for coolingfor 24 hours, 280 ml of DMF was added and the insoluble matter wasfiltered off, followed by washing with 2.5 liters of methanol fourtimes. The filtrate and the wash liquid were combined and insolublematter was filtered off. To the filtrate was added 16 liters of water,followed by stirring for 24 hours, and the precipitate was collected byfiltration and washed with water. Then, the collected precipitate wasdissolved in 2.1 liters of acetone, and, thereafter, a small amount ofinsoluble matter was filtered off. To the filtrate was added 16 litersof water, followed by stirring for 2 hours. Then, the precipitate wascollected by filtration and washed with water to obtain 34.5 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.34      (1H, S) 7.04-8.67     (5H, m)    3.60       (3H, S) 2.96-3.53     (2H, m)    2.25-2.79  (2H, m)    ______________________________________

EXAMPLE 4

Preparation of2-hydroxy-6-amidino-1-(2-carbamoylethyl)naphthalene.hydrochloride:

34.5 Grams of methyl 3-(2-hydroxy-6-cyano-1-naphthyl)propionate wasslowly added to 360 ml of anhydrous methanol solution saturated withhydrogen chloride gas with stirring under cooling with ice, followed byfurther stirring for 24 hours under cooling with water. Then, hydrogenchloride gas was passed therethrough for 2 hours, followed by furtherstirring for 48 hours. The precipitate was collected by filtration andwashed with a small amount of acetone. The collected precipitate wasslowly added to 960 ml of anhydrous methanol saturated with ammonia gaswith stirring under cooling with ice, followed by further stirring for48 hours at room temperature. The precipitate was collected byfiltration and washed with a small amount of acetone. Then, theprecipitate was added to 60 ml of water. With stirring at roomtemperature, 10% hydrochloric acid was added dropwise little by littleto render the solution acidic, followed by stirring for 2.5 hours. Theprecipitate was collected by filtration and washed with a small amountof acetone to obtain 26.1 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.44   (4H, brs)     8.46      (1H, S)    8.11   (1H, d, J = 9.2 Hz)                         7.69-7.98 (2H, m)    7.50   (1H, S)       7.41      (1H, d, J = 8.9 Hz)    6.91   (1H, S)       3.02-3.36 (2H, m)    3.02-3.36           (2H, m)       2.21-2.48 (2H, m)    ______________________________________

EXAMPLE 5

Preparation of 6-amidino-1-(2-carbamoylethyl)-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoate.dihydrochloride:

45 Milliliters of 20% hydrous pyridine was added to 2.71 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.hydrochloride, 3.0 g of6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloride, 2.52 g of DCCand 124.6 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and 6 days under cooling with water. The precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 15 ml of DMF, and a small amount of insolublematter was filtered off. The filtrate was added dropwise to 400 ml ofacetone, followed by stirring for 1 hour under cooling with ice and 24hours under cooling with water. The supernatant was decanted, and to theresidue was added 15 ml of methanol, followed by stirring for 1 hourunder cooling with ice. The precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using a mixed liquid of methyl ethylketone-water-acetic acid (80:15:5) as an eluent solvent, and the desiredfractions were collected and the solvent was distilled off under reducedpressure. The residue was dissolved in 5 ml of DMF and 200 μl ofconcentrated hydrochloric acid, and the solution was added dropwise to200 ml of acetone. After stirring for 1 hour under cooling with ice andthen 24 hours under cooling with water, the precipitate was collected byfiltration to obtain 495.4 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    8.62   (1H, d, J = 2.0 Hz)                         8.42      (1H, d, J = 9.2 Hz)    8.35   (2H, d, J = 8.6 Hz)                         8.18      (1H, d, J = 9.2 Hz)    8.00   (1H, dd, J1 = 8.9,           J2 = 1.7 Hz)    7.64   (1H, d, J = 8.9 Hz)                         7.56      (1H, d, J = 8.6 Hz)    3.81   (4H, S)       3.21-3.44 (2H, m)    2.43-2.57           (2H, m)    ______________________________________

EXAMPLE 6

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 3-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoate.dihydrochloride:

15 Milliliters of 20% hydrous pyridine was added to 634.1 mg of 3-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.hydrochloride, 676.7 mgof 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 598 mg of DCCand 29.5 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 24 hours under cooling with water. Thereafter, the sameprocedure as in Example 1 was carried out to obtain 439.5 mg of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.39     (1H, S)      9.70       (2H, S)    9.51      (2H, S)      8.66       (2H, S)    8.33      (1H, d, J = 8.9 Hz)                           7.90-8.17  (5H, m)    7.54-7.86 (3H, m)      7.03       (1H, S)    4.03      (2H, S)      3.70       (4H, S)    ______________________________________

EXAMPLE 7

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-hydroxyethyl)aminoiminomethylamino!-benzoate.dihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 1.02 g of 4-(2-hydroxyethyl)aminoiminomethylamino!benzoic acid.hydrochloride, 1.0 gof 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 884 mg of DCCand 43.6 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 24 hours at room temperature. Thereafter, the sameprocedure as in Example 1 was carried out to obtain 1.17 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.58  (1H, S)        9.67     (2H, S)    9.45   (2H, S)        8.65     (1H, d, J = 1.7 Hz)    8.42   (1H, brs)      7.83-8.36                                   (8H, m)    7.69   (1H, S)        7.64     (1H, d, J = 8.9 Hz)    7.49   (2H, d, J = 8.6 Hz, m)    7.03   (1H, S)        3.98     (2H, S)    3.53-3.63           (2H, m)        3.29-3.51                                   (2H, m)    ______________________________________

EXAMPLE 8

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-morpholinomethylbenzoate.dihydrochloride:

15 Milliliters of anhydrous pyridine was added to 612.2 mg of4-morpholinomethylbenzoic acid, 703.9 mg of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 622.6 mg of DCCand 30.7 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 3 days under cooling with water. Thereafter, the sameprocedure as in Example 1 was carried out to obtain 440.7 mg of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    12.15     (1H, S) 9.66       (2H, S)    9.46      (2H, S) 8.64       (1H, S)    8.22-8.52 (3H, m) 8.11       (1H, d, J = 8.9 Hz)    7.87-8.04 (3H, m) 7.48-7.80  (2H, m)    7.02      (1H, S) 4.49       (2H, S)    4.00      (2H, S) 3.94       (4H, S)    3.08-3.36 (4H, m)    ______________________________________

EXAMPLE 9

Preparation of 6-amidino-1-(2-carbamoylethyl)-2-naphthyl 4-(2-hydroxyethyl)aminoiminomethylamino!-benzoate.dihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 1.45 g of 4-(2-hydroxyethyl)aminoiminomethylamino!benzoic acid.hydrochloride, 1.5 gof 6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloric acid, 1.26 gof DCC and 62.3 mg of DMAP, followed by stirring for 2 hours undercooling with ice and then 24 hours at room temperature. Thereafter, thesame procedure as in Example 1 was effected to obtain 1.17 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.59     (1H, S) 9.70       (2H, S)    9.48      (2H, S) 8.68       (1H, S)    7.84-8.52 (7H, m) 7.60       (1H, d, J = 8.9 Hz)    7.34-7.57 (3H, m) 6.84       (1H, brs)    3.55-3.69 (2H, m) 3.36-3.52  (2H, m)    3.13-3.34 (2H, m) 2.29-2.48  (2H, m)    ______________________________________

EXAMPLE 10

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-guanidinobenzoate.hydrochloric acid methanesulfonate:

100 Milliliters of 20% hydrous pyridine was added to 3.0 g of4-guanidinobenzoic acid.methanesulfonate, 3.0 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride and 4.5 g of DCC,followed by stirring for 2 hours under cooling with ice and then 2 daysat room temperature. The precipitate was filtered and 1 g of activecarbon was added to the filtrate, followed by stirring for 30 minutesunder cooling with ice, and insoluble matter was filtered off. Thefiltrate was slowly added dropwise to 4 liters of ether under coolingwith ice, followed by stirring for 2 hours. The precipitate wascollected by filtration and washed with 100 ml of acetone to obtain acrude product. Then, the product was dissolved in 150 ml of methanol.Thereafter, 2.5 g of active carbon was added to the solution, followedby stirring for 30 minutes under cooling with ice, and insoluble matterwas filtered off. The filtrate was slowly added dropwise to 1 liter ofacetone under cooling with ice, followed by stirring for 2 hours. Theprecipitate was collected by filtration to obtain 2.9 g of the desiredproduct.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.48     (5H, brs)                      6.55-8.72     (15H, m)    3.98     (2H, S)  2.45          (3H, S)    ______________________________________

EXAMPLE 11

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-nitrobenzoate.hydrochloride:

30 Milliliters of anhydrous pyridine and 10 ml of DMF were added to 1.8g of 4-nitrobenzoic acid, 3.0 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.7 g of DCC and130.9 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 24 hours at room temperature. Then, the precipitate wascollected by filtration and washed with a small amount of DMF. To thiscollected precipitate was added 100 ml of DMF, to dissolve theprecipitate with heating, followed by stirring for 2 hours under coolingwith ice. Then, insoluble matter was filtered off and the filtrate wasconcentrated to 20 ml under reduced pressure. The residue was addeddropwise to 400 ml of acetone, followed by stirring for 24 hour undercooling with ice. The precipitate was collected by filtration to obtaina crude product. Then, the product was subjected to silica gel columnchromatography using chloroformmethanol-acetic acid (80:15:5) as aneluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. The residue was suspended withaddition of 20 ml of methanol and 0.6 ml of concentrated hydrochloricacid, and the suspension was added dropwise to a mixed liquid of 200 mlof ether and 20 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain 1.35 g of 6-amidino-1-carbamoylmethyl-2-naphthyl4-nitrobenzoate.hydrochloride.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.66   (2H, S)    7.96   (1H, dd, J1 = 8.9,           J2= 1.7 Hz)    9.45   (2H, S)      7.71      (1H, d, J = 8.9 Hz)    8.64   (1H, d, J = 1.7 Hz)                        7.70      (1H, S)    8.45   (4H, S)      7.01      (1H, S)    8.36   (1H, d, J = 8.9 Hz)                        4.02      (2H, S)    8.12   (1H, d, J = 8.9 Hz)    ______________________________________

EXAMPLE 12

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-aminobenzoate.dihydrochloride;

To 600 mg of 6-amidino-1-carbamoylmethyl-2-naphthyl4-nitrobenzoate.hydrochloride were added 10 ml of anhydrous DMF and 100mg of 10% palladium carbon, and catalytic reduction was effected at roomtemperature for 24 hours. Then, insoluble matter was filtered off andthe filtrate was concentrated under reduced pressure. To the residue wasadded 15 ml of methanol, and, furthermore, 350 μl of concentratedhydrochloric acid was added with stirring under cooling with ice. Then,the resulting solution was added dropwise to 200 ml of acetone, followedby stirring for 1 hour under cooling with ice. Then, the precipitate wascollected by filtration to obtain 572.7 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.64     (2H, S)      7.58    (2H, d, J = 8.9 Hz)    9.43     (2H, S)      7.04    (3H, brs)    8.62     (1H, d, J = 1.7 Hz)                          6.96    (1H, S)    8.26     (1H, d, J = 8.9 Hz)                          6.91    (2H, d, J = 8.6 Hz)    8.06     (1H, d, J = 8.9 Hz)                          3.95    (2H, S)    7.83-8.03             (3H, m)    ______________________________________

EXAMPLE 13

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl2-nitrobenzoate.hydrochloride:

50 Milliliters of anhydrous pyridine and 20 ml of DMF were added to 5.0g of 2-nitrobenzoic acid, 3.0 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 4.4 g of DCC and218.2 mg of DMAP, followed by stirring for 2 hours under cooling withice and 24 hours at room temperature. Then, the precipitate was filteredand washed with 100 ml of warm DMF. This wash liquid and the filtratewere combined, and the solvent was distilled off under reduced pressure.To the residue was added 20 ml of DMF, and the resulting solution wasadded dropwise to 600 ml of acetone, followed by stirring for 2 hoursunder cooling with ice. Then, the precipitate was collected byfiltration to obtain a crude product. Then, the product was subjected tosilica gel column chromatography using chloroformmethanol-acetic acid(80:15:5) as an eluent, and the desired fractions were collected and thesolvent was distilled off under reduced pressure. To 1/2 of the residuewere added 20 ml of methanol and 1.4 ml of concentrated hydrochloricacid to suspend the residue. The suspension was added dropwise to amixed liquid of 200 ml of ether and 200 ml of acetone, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain 2.42 g of6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.hydrochloride.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.65   (2H, S)       7.88-8.09 (3H, m)    9.43   (2H, S)       7.75      (1H, S)    8.63   (1H, d, J = 1.7 Hz)                         7.66      (1H, d, J = 8.9 Hz)    8.35   (1H, d, J = 8.9 Hz)                         7.08      (1H, S)    8.10-8.30           (3H, m)       4.02      (2H, S)    ______________________________________

EXAMPLE 14

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl2-aminobenzoate.hydrochloride:

To the other 1/2 of the residue in Example 13 was added 20 ml ofmethanol to suspend the residue, and the resulting suspension was addeddropwise to a mixed liquid consisting of 150 ml of ether and 150 ml ofacetone, followed by stirring for 24 hours under cooling with ice. Then,the precipitate was collected by filtration to obtain 1.80 g of6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.acetate. To 1.0 gof 6-amidino-1-carbamoylmethyl-2-naphthyl 2-nitrobenzoate.acetate wereadded 50 ml of anhydrous DMF and 200 mg of 10% palladium carbon, andcatalytic reduction was effected at room temperature for 24 hours. Then,insoluble matter was filtered off and the filtrate was concentratedunder reduced pressure. To the residue was added 20 ml of methanol, and0.6 ml of concentrated hydrochloric acid was added thereto understirring and cooling with ice. Then, the resulting solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using chloroformmethanol-acetic acid (80:15:5) asan eluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. The residue was dissolved in 20 mlof methanol and 0.6 ml of concentrated hydrochloric acid, and thesolution was added dropwise to 350 ml of acetone, followed by stirringfor 24 hours under cooling with ice. Then, the precipitate was collectedby filtration to obtain 344.6 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.62 (2H, S)       7.26-7.44 (1H, m)    9.41 (2H, S)       7.03 (1H, S)    8.61 (1H, d, J=1.7 Hz)                       6.88 (1H, d, J=8.6 Hz)    8.28 (1H, d, J=8.9 Hz)                       6.79 (2H, S)    7.85-8.14 (3H, m)  6.57-6.71 (1H, m)    7.64 (1H, S)       3.95 (2H, S)    7.59 (1H, d, J=8.9 Hz)    ______________________________________

EXAMPLE 15

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-dimethylaminobenzoate.dihydrochloride:

40 Milliliters of 20% hydrous pyridine was added to 3.0 g of4-dimethylaminobenzoic acid, 1.77 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 2.65 g of DCC and130.9 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 24 hours at room temperature. Then, the precipitate wascollected by filtration and washed with a small amount of pyridine. Tothis collected precipitate were added 60 ml of DMF and 20 ml of water todissolve the precipitate with heating, followed by stirring for 2 hoursunder cooling with ice. Then, insoluble matter was filtered off and thefiltrate was concentrated under reduced pressure. To the residue wereadded 15 ml of DMF and 10 ml of water to dissolve the residue. Thesolution was added dropwise to 400 ml of acetone, followed by stirringfor 24 hour under cooling with ice. The precipitate was collected byfiltration to obtain a crude product. Then, the product was subjected tosilica gel column chromatography using methyl ethyl ketone-water-aceticacid (80:15:5) as an eluent, and the desired fractions were collectedand the solvent was distilled off under reduced pressure. The residuewas suspended in 15 ml of methanol, 5 ml of DMF and 0.9 ml ofconcentrated hydrochloric acid, and the suspension was added dropwise toa mixed liquid of 200 ml of acetone and 100 ml of ether, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain 1.96 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.67 (2H, S)       7.63 (1H, brs)    9.47 (2H, S)       7.58 (1H, d, J=8.9 Hz)    8.63 (1H, d, J=1.7 Hz)                       7.03 (1H, brs)    8.25 (1H, d, J=8.9 Hz)                       6.85 (3H, d, J=9.2 Hz)    8.06 (1H, d, J=8.9 Hz)                       3.94 (2H, S)    8.00 (2H, d, J=9.2 Hz)                       3.06 (6H, S)    7.95 (1H, dd, J=8.9, J2=1.7 Hz)    ______________________________________

EXAMPLE 16

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-acetylaminoethyl)aminoiminomethylamino!-benzoate.dihydrochloride:

40 Milliliters of 10% hydrous pyridine was added to 1.5 g of 4-(2-acetylaminoethyl)aminoiminomethylamino!benzoic acid.hydrochloride,1.12 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.55 gof DCC and 61 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and then 48 hours at room temperature. The precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 15 ml of methanol, and this solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hour undercooling with ice. The precipitate was collected by filtration to obtaina crude product. Then, the product was subjected to silica gel columnchromatography using methyl ethyl ketone-water-acetic acid (80:15:5) asan eluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. To the residue were added 15 ml ofmethanol and 0.96 ml of concentrated hydrochloric acid, and the solutionwas added dropwise to 400 ml of acetone, followed by stirring for 24hours under cooling with ice. Then, the precipitate was collected byfiltration to obtain 1.24 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.60 (1H, S)      7.69 (1H, S)     9.65 (2H, S)      7.64 (1H, d, J=8.9 Hz)     9.43 (2H, S)      7.49 (2H, d, J=8.6 Hz)     8.64 (1H, d, J=1.7 Hz)                       7.04 (1H, S)     8.47 (1H, brs)    3.98 (2H, S)     8.17-8.38 (5H, m) 3.17-3.55 (4H, m)     8.10 (1H, d, J=8.9 Hz)                       1.87 (3H, S)     7.96 (1H, dd, J1-8.9, J2=1.7 Hz)    ______________________________________

EXAMPLE 17

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-dimethylaminoethyl)aminoiminomethylamino!benzoate.trihydrochloride:

40 Milliliters of 20% hydrous pyridine was added to 1.5 g of 4-(2-dimethylaminoethyl)aminoiminomethylamino!benzoicacid.dihydrochloride, 1.03 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.44 g of DCC and56 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. The precipitate was filtered andthe filtrate was concentrated under reduced pressure. To the residue wasadded 15 ml of methanol, and this solution was added dropwise to 400 mlof acetone, followed by stirring for 24 hours under cooling with ice.Then, the precipitate was collected by filtration to obtain a crudeproduct. Then, the product was subjected to silica gel columnchromatography using methyl ethyl ketone-water-acetic acid (80:15:5) asan eluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. To the residue were added 15 ml ofmethanol and 1.41 ml of concentrated hydrochloric acid, and the solutionwas added dropwise to 400 ml of acetone, followed by stirring for 24hours under cooling with ice. Then, the precipitate was collected byfiltration to obtain 1.52 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.97 (1H, brs)     7.97 (1H, dd, J1=8.9, J2=1.7 Hz)    10.80 (1H, S)      7.72 (1H, S)     9.678 (2H, S)     7.64 (1H, d, J=8.9 Hz)     9.46 (2H, S)      7.54 (2H, d, J=8.6 Hz)     8.65 (2H, d, J=1.7 Hz)                       7.04 (1H, S)     8.49 (1H, brs)    3.98 (2H, S)     8.30 (1H, d, J=8.9 Hz)                       3.72-3.94 (2H, m)     8.22 (2H, d, J=8.6 Hz)                       3.24-3.49 (2H, m)     8.10 (1H, d, J=8.9 Hz)                       2.84 (6H, d, J=3.0 Hz)    ______________________________________

EXAMPLE 18

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-methoxyethyl)aminoiminomethylamino!-benzoate.dihydrochloride:

50 Milliliters of 10% hydrous pyridine was added to 1.5 g of 4-(2-methoxyethyl)aminoiminomethylamino!benzoic acid.hydrochloride, 1.22 gof 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.7 g of DCCand 67 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 24 hours at room temperature. The precipitate was filteredand the filtrate was concentrated under reduced pressure. To the residuewas added 15 ml of ethanol and 15 ml of isopropanol, and the precipitatewas collected by filtration. To the collected precipitate were added 15ml of DMF and 1.34 ml of concentrated hydrochloric acid to dissolve theprecipitate. Furthermore, 1 g of active carbon was added, followed bystirring for 2 hours at room temperature. The insoluble matter wasfiltered off and the filtrate was added dropwise to 400 ml of acetone,followed by stirring for 24 hour under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 15 ml of methanol and 1.34ml of concentrated hydrochloric acid, and the solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain 1.25 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.61 (1H, brs)    7.64 (1H, d, J=8.9 Hz)     9.67 (2H, S)      7.47 (2H, d, J=8.6 Hz)     9.45 (2H, S)      7.04 (1H, S)     8.65 (1H, d, J=1.7 Hz)                       3.98 (2H, S)     8.48 (1H, brs)    3.52 (4H, S)     7.85-8.44 (7H, m) 3.33 (3H, S)     7.70 (1H, S)    ______________________________________

EXAMPLE 19

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-(morpholinoaminoiminomethylamino)-benzoate.dihydrochloride:

55 Milliliters of 10% hydrous pyridine was added to 1.5 g of4-morpholinoaminoiminomethylamino-benzoic acid.hydrochloride, 1.12 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.55 g of DCC and61 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. The precipitate was filtered andthe filtrate was concentrated under reduced pressure. To the residue wasadded 15 ml of methanol, and the solution was added dropwise to 400 mlof ether, followed by stirring for 24 hours under cooling with ice.Then, the precipitate was collected by filtration to obtain a crudeproduct. Then, the product was subjected to silica gel columnchromatography using methyl ethyl ketone-water-acetic acid (80:15:5) asan eluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. To the residue were added 20 ml ofmethanol and 2.07 ml of concentrated hydrochloric acid, and the solutionwas added dropwise to a mixed liquid of 200 ml of ether and 200 ml ofacetone, followed by stirring for 24 hours under cooling with ice. Then,the precipitate was collected by filtration to obtain 1.42 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.82 (1H, brs)    7.70 (1H, S)     9.92 (1H, brs)    7.64 (1H, d, J=8.9 Hz)     9.66 (2H, s)      7.49 (2H, d, J=8.6 Hz)     9.45 (2H, S)      7.04 (1H, S)     8.64 (1H, d, J=1.7 Hz)                       3.98 (2H, S)     8.18-8.60 (5H, m) 3.74 (4H, brs)     8.11 (1H, d, J=8.9 Hz)                       2.89 (4H, brs)     7:96 (1H, dd, J1=8.9, J2=1.7 Hz)    ______________________________________

EXAMPLE 20

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-morpholinoethyl)aminoiminomethylamino)-benzoate.trihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.2 g of 4-(2-morpholinoethyl)aminoiminomethylamino!benzoic acid.dihydrochloride,1.72 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.06 gof DCC and 52.4 mg of DMAP, followed by stirring for 2 hours undercooling with ice and then 48 hours at room temperature. The precipitatewas filtered and the filtrate was concentrated under reduced pressure.To the residue was added 15 ml of DMF, and the solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using methyl ethyl ketone-water-formic acid(80:15:5) as an eluent, and the desired fractions were collected and thesolvent was distilled off under reduced pressure. To the residue wereadded 15 ml of methanol and 2.2 ml of concentrated hydrochloric acid,and the solution was added dropwise to 450 ml of acetone, followed bystirring for 15 minutes under cooling with ice. Then, the precipitatewas collected by filtration to obtain 840 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.59 (1H, brs)    8.10 (1H, d, J=8.9 Hz)    10.77 (1H, S)     7.95 (1H, dd, J1=8.9, J2=1.7 Hz)     9.66 (2H, S)      7.69 (1H, S)     9.44 (2H, S)      7.64 (1H, d, J=8.9 Hz)     8.68 (1H, S)      7.53 (2H, d, J=8.6 Hz)     8.64 (1H, d, J=1.7 Hz)                       7.03 (1H, S)     8.48 (2H, brs)    3.73-4.14 (8H, m)     8.30 (1H, d, J=8.9 Hz)                       3.00-3.65 (6H, m)     8.22 (2H, d, J=8.6 Hz)    ______________________________________

EXAMPLE 21

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(3-morpholinopropyl)aminoiminomethylamino)benzoate.trihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.2 g of 4-(3-morpholinopropyl)aminoiminomethylamino!benzioc acid.dihydrochloride,1.79 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.06 gof DCC and 52.4 mg of DMAP, followed by stirring for 2 hours undercooling with ice and then 48 hours at room temperature. The precipitatewas filtered and the filtrate was concentrated under reduced pressure.To the residue was added 30 ml of DMF, and the solution was addeddropwise to a mixed liquid of 300 ml of acetone and 100 ml of ether,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 30 ml of methanol and 792 μlof concentrated hydrochloric acid, and the solution was added dropwiseto 400 ml of acetone, followed by stirring for 24 hours under coolingwith ice. Then, the precipitate was collected by filtration to obtain1.07 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.57 (1H, brs)     7.96 (1H, dd, J1=8.9, J2=1.7 Hz)    10.70 (1H, S)      7.70 (1H, S)     9.66 (2H, S)      7.64 (1H, d, J=8.9Hz)     9.44 (2H, S)      7.50 (2H, d, J=8.6Hz)     8.64 (1H, d, J=1.7 Hz)                       7.03 (1H, S)     8.60 (1H, brs)    3.75-4.09 (6H, m)     8.36 (1H, brs)    3.34-3.57 (4H,m)     8.30 (1H, d, J=8.9 Hz)                       2.92-3.29 (4H, m)     8.23 (2H, d, J=8.6 Hz)                       1.92-2.18 (2H, m)     8.10 (1H, d, J=8.9 Hz)    ______________________________________

EXAMPLE 22

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(3-morpholinopropyl)iminomethylaminomethylamino)benzoate-trihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 1.13 g of 4-(3-morpholinopropyl)iminomethylaminothylamino!benzoicacid.dihydrochloride, 800 mg of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 708 mg of DCC and34.9 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. Furthermore, 354 mg of DCC wasadded, followed by stirring for 24 hours at room temperature. Theprecipitate was filtered and the filtrate was concentrated under reducedpressure. To the residue was added 30 ml of DMF, and the solution wasadded dropwise to a mixed liquid of 300 ml of acetone and 100 ml ofether, followed by stirring for 24 hours under cooling with ice. Then,the precipitate was collected by filtration to obtain a crude product.Then, the product was subjected to silica gel column chromatographyusing methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, andthe desired fractions were collected and the solvent was distilled offunder reduced pressure. To the residue were added 5 ml of DMF and 716 μlof concentrated hydrochloric acid, and the solution was added dropwiseto a mixed liquid of 250 ml of acetone and 100 ml of ether, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain 972.7 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.56 (1H, brs)    7.55 (2H, d, J=8.6 Hz)    10.42 (1H, S)      7.04 (1H, S)     9.66 (2H, S)      3.72-4.17 (6H, m)     9.44 (2H, S)      3.28-3.65 (4H, m)     7.84-8.90 (8H, m) 2.80-3.26 (7H, m)     7.71 (1H, S)      1.90-2.22 (2H, m)     7.63 (1H, d, J=8.9 Hz)    ______________________________________

EXAMPLE 23

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(4-morpholinobutyl)aminoiminomethylamino!-benzoate.trihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 1.05 g of 4-(4-morpholinobutyl)aminoiminomethylamino!benzoic acid.dihydrochloride,735.7 mg of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 660 mgof DCC and 32.6 mg of DMAP, followed by stirring for 2 hours undercooling with ice and then 48 hours at room temperature. The precipitatewas filtered and the filtrate was concentrated under reduced pressure.To the residue was added 5 ml of DMF, and the solution was addeddropwise to 400 ml of acetone, followed by stirring for 1 hour undercooling with ice. Then, the precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using methyl ethyl ketone-water-formic acid(80:15:5) as an eluent, and the desired fractions were collected and thesolvent was distilled off under reduced pressure. To the residue wereadded 10 ml of methanol and 1.2 ml of concentrated hydrochloric acid,and the solution was added dropwise to 400 ml of acetone, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain 885.3 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.52 (1H, brs)     7.96 (1H, dd, J1=8.9, J2=1.7 Hz)    10.66 (1H, S)      7.70 (1H, S)     9.66 (2H, S)      7.64 (1H, d, J=8.9 Hz)     9.45 (2H, S)      7.48 (2H, d, J=8.6 Hz)     8.65 (1H, d, J=1.7 Hz)                       7.03 (1H, S)     8.61 (1H, brs)    3.74-4.12 (6H, m)     8.15-8.45 (5H, m) 2.84-3.56 (8H, m)     8.10 (1H, d, J=8.9 Hz)                       1.49-1.97 (4H, m)    ______________________________________

EXAMPLE 24

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-2-(1-pyrrolidinyl)ethyl!aminoiminomethylamino!benzoate.trihydrochloride

30 Milliliters of 20% hydrous pyridine was added to 1.51 g of 4-2-(1-pyrrolidinyl)ethyl!aminoiminomethylamino!benzoicacid.dihydrochloride, 1.1 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 973 mg of DCC and48 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. The precipitate was filtered andthe filtrate was concentrated under reduced pressure. To the residue wasadded 15 ml of DMF, and the solution was added dropwise to 300 ml ofacetone, followed by stirring for 24 hours under cooling with ice. Then,the precipitate was collected by filtration to obtain a crude product.Then, the product was subjected to silica gel column chromatographyusing methyl ethyl ketone-water-formic acid (80:15:5) as an eluent, andthe desired fractions were collected and the solvent was distilled offunder reduced pressure. To the residue were added 20 ml of methanol and3.7 ml of concentrated hydrochloric acid, and the solution was addeddropwise to 200 ml of acetone, followed by stirring for 2 hours undercooling with ice. Then, the precipitate was collected by filtration, andto the collected precipitate were added 5 ml of ethanol and then 10 mlof methanol, followed by stirring for 1 hour under cooling with ice. Theprecipitate was collected by filtration and washed with a small amountof acetone to obtain 1.21 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.18(1H, brs)     8.10(1H, d, J=8.9Hz)    10.75(1H, S)       7.97(1H, d, J=8.9Hz)    9.67(2H, S)        7.70(1H, S)    9.45(2H, S)        7.64(1H, d, J=8.9Hz)    8.69(2H, S)        7.53(2H, d, J=8.6Hz)    8.65(1H, S)        7.04(1H, S)    8.48(1H, brs)      3.98(2H, S)    8.30(1H, d, J=8.9Hz)                       2.92-3.91(8H, m)    8.22(2H, d, J=8.6Hz)                       1.73-2.14(4H, m)    ______________________________________

EXAMPLE 25

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(2-piperidinoethyl)aminoiminomethylamino!-benzoate.trihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.71 g of 4-(2-piperidinoethyl)aminoiminomethylamino!benzoic acid.dihydrochloride,1.2 g of 6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.06 g ofDCC and 52.4 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and then 4 days at room temperature. The precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 15 ml of DMF, and the solution was added dropwiseto a mixed liquid of 300 ml of acetone and 100 ml of ether, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain a crude product. Then, the product wassubjected to silica gel column chromatography using methyl ethylketone-water-formic acid (80:15:5) as an eluent, and the desiredfractions were collected and the solvent was distilled off under reducedpressure. To the residue were added 20 ml of methanol and 2.1 ml ofconcentrated hydrochloric acid, and the solution was added dropwise to450 ml of acetone, followed by stirring for 30 minutes under coolingwith ice. Then, the precipitate was collected by filtration to obtain1.08 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.86(1H, brs)       8.10(1H, d, J=8.9Hz)    10.79(1H, S)    7.97(1H, dd, J1=8.9, J2=1.7Hz)    9.67(2H, S)          7.70(1H, S)    9.46(2H, S)          7.64(1H, d, J=8.9Hz)    8.71(1H, brs)        7.52(2H, d, J=8.6Hz)    8.65(1H, d, J=1.7Hz) 7.04(1H, S)    8.48(2H, brs)        3.72-4.10(4H, m)    8.30(1H, d, J=8.9Hz) 2.70-3.60(8H, m)    8.22(2H, d, J=8.6Hz) 1.57-2.01(4H, m)    ______________________________________

EXAMPLE 26

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-methylaminoiminomethylaminobenzoate.dihydrochloride:

20 Milliliters of 20% hydrous pyridine was added to 600 mg of4-methylaminoiminomethylaminobenzoic acid.hydrochloride, 730 mg of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 646 mg of DCC and32 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 48 hours at room temperature. The precipitate was filtered andthe filtrate was concentrated under reduced pressure. To the residue wasadded 20 ml of DMF, and the solution was added dropwise to 300 ml ofacetone, followed by stirring for 24 hours under cooling with ice. Then,the precipitate was collected by filtration to obtain a crude product.Then, the product was subjected to silica gel column chromatographyusing methyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, andthe desired fractions were collected and the solvent was distilled offunder reduced pressure. To the residue were added 15 ml of methanol and440 μl of concentrated hydrochloric acid, and the solution was addeddropwise to a mixed liquid of 300 ml of acetone and 100 ml of ether,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain 661.1 mg of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.64(1H, brs)     7.63(1H, d, J=8.9Hz)    9.67(2H, S)        7.47(2H, d, J=8.6Hz)    9.46(2H, S)        7.03(1H, S)    8.64(1H, d, J=1.7Hz)                       3.98(2H, S)    7.86-8.54(8H, m)   2.91(3H, d, J=4.6Hz)    7.69(1H, S)    ______________________________________

EXAMPLE 27

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-methylaminomethyliminomethylaminobenzoate.dihydrochloride:

80 Milliliters of 20% hydrous pyridine was added to 5.76 g of4-methylaminomethyliminomethylaminobenzoic acid.hydrochloride, 6.0 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 5.3 g of DCC and217 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 5 days at room temperature. Then, the precipitate was collectedby filtration and washed with 120 ml of warm DMF. To this collectedprecipitate was added 300 ml of water, followed by stirring for 24 hoursat room temperature, and the precipitate was filtered. Each of thereaction filtrate, warm DMF wash liquid and aqueous filtrate obtainedabove was concentrated under reduced pressure. The resulting residueswere combined and 70 ml of DMF was added thereto. The solution was addeddropwise to 700 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using methyl ethyl ketone-water-acetic acid(80:15:5) as an eluent, and the desired fractions were collected and thesolvent was distilled off under reduced pressure. To the residue wereadded 50 ml of methanol and 3.3 ml of concentrated hydrochloric acid,and the solution was added dropwise to a mixed liquid of 500 ml ofacetone and 200 ml of ether, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain 5.78 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.31(1H, S)    7.97(1H, dd, J1=8.9, J2=1.7Hz)    9.69(2H, S)          7.73(1H, S)    9.48(2H, S)          7.63(1H, d, J=8.9Hz)    8.66(1H, d, J=1.7Hz) 7.51(2H, d, J=8.6Hz)    8.40(2H, brs)        7.05(1H, S)    8.30(1H, d, J=8.9Hz) 3.98(2H, S)    8.21(2H, d, J=8.6Hz) 2.94(6H, S)    8.10(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 28

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-n-butylaminoiminomethylaminobenzoate.dihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.6 g of4-n-butylaminoiminomethylaminobenzoic acid.hydrochloride, 1.5 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.33 g of DCC and65.5 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 4 days at room temperature. Then, the precipitate was filteredand the filtrate was concentrated under reduced pressure. To the residuewas added 20 ml of DMF, and the solution was added dropwise to a mixedliquid of 300 ml of acetone and 200 ml of ether, followed by stirringfor 24 hours under cooling with ice. Then, the precipitate was collectedby filtration to obtain a crude product. Then, the product was subjectedto silica gel column chromatography using methyl ethylketone-water-acetic acid (80:15:5) as an eluent, and the desiredfractions were collected and the solvent was distilled off under reducedpressure. To the residue were added 30 ml of methanol and 2.1 ml ofconcentrated hydrochloric acid, and the solution was added dropwise to250 ml of acetone, followed by stirring for 24 hours under cooling withice. Then, the precipitate was collected by filtration, and to thecollected precipitate were added 9 ml of methanol, 7 ml of ethanol and 6ml of 2-propanol, followed by stirring for 1 hour under cooling withice. The precipitate was collected by filtration and washed with a smallamount of acetone to obtain 1.68 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.59(1H, S)       7.63(1H, d, J=8.9Hz)    9.66(2H, S)        7.46(2H, d, J=8.6Hz)    9.44(2H, S)        7.03(1H, S)    8.64(1H, d, J=1.7Hz)                       3.98(2H, S)    8.53(1H, brs)      3.20-3.45(2H, m)    7.85-8.45(7H, m)   1.24-1.67(4H, m)    7.68(1H, S)        0.92(3H, t, J=7.3Hz)    ______________________________________

EXAMPLE 29

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-dimethylaminoiminomethylaminobenzoate.dihydrochloride:

40 Milliliters of 20% hydrous pyridine was added to 1.44 g of4-dimethylaminoiminomethylaminobenzoic acid.hydrochloride, 1.5 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.33 g of DCC and65.5 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 72 hours at room temperature. Then, the precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 25 ml of DMF, and the resulting solution was addeddropwise to a mixed liquid of 200 ml of ether and 100 ml of acetone,followed by stirring for 2 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-formic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 15 ml of methanol and 2.8 mlof concentrated hydrochloric acid, and the resultant solution was addeddropwise to 150 ml of acetone, followed by stirring for 2 hours undercooling with ice. Then, the precipitate was collected by filtration, andto the collected precipitate were added 10 ml of methanol and 5 ml ofethanol, followed by stirring for 2 hours under cooling with ice. Theprecipitate was collected by filtration and washed with a small amountof acetone to obtain 966 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.43(1H, S)    7.97(1H, dd, J1=8.9, J2=1.7Hz)    9.69(2H, S)          7.71(1H, S)    9.48(2H, S)          7.63(1H, d, J=8.9Hz)    8.66(1H, d, J=1.7Hz) 7.48(2H, d, J=8.6Hz)    8.25-8.40(3H, m)     7.04(1H, S)    8.21(2H, d, J=8.9Hz) 3.98(2H, S)    8.10(1H, d, J=8.9Hz) 3.14(6H, S)    ______________________________________

EXAMPLE 30

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl4-aminoiminomethylbenzoate.dihydrochloride:

20 Milliliters of 20% hydrous pyridine and 6 ml of DMF were added to 1.0g of 4-aminoiminomethylbenzoic acid.hydrochloride, 1.39 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.23 g of DCC and60.8 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. Then, the precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 20 ml of DMF, and the resulting solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain a crude product. Then, the product was subjected to silica gelcolumn chromatography using methyl ethyl ketone-water-formic acid(80:15:5) as an eluent, and the desired fractions were collected and thesolvent was distilled off under reduced pressure. To the residue wereadded 10 ml of methanol and 0.9 ml of concentrated hydrochloric acid,and the resulting solution was added dropwise to 200 ml of acetone,followed by stirring for 2 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain 80.2 mg of the desiredproduct.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.70(2H, S)        8.03-8.18(3H, m)    9.61(2H, S)        7.909-8.00(1H, m)    9.48(2H, S)        7.70(1H, d, J=8.9Hz)    9.36(2H, S)        7.65(1H, S)    8.62(1H, S)        7.00(1H, S)    8.28-8.46(3H, m)   4.01(2H, S)    ______________________________________

EXAMPLE 31

Preparation of 6-amidino-1-carbamoylmethyl-2-naphthyl 4-(4,5-dihydrothiazol-2-yl)amino!-benzoate.dihydrochloride:

15 Milliliters of 20% hydrous pyridine was added to 1.5 g of 4-(4,5-dihydrothiazol-2-yl)amino!benzoic acid.hydrochloride, 1.62 g of6-amidino-1-carbamoylmethyl-2-naphthol.hydrochloride, 1.43 g of DCC and70.8 mg of DMAP, followed by stirring for 2 hours under cooling with iceand then 24 hours at room temperature. Then, the precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 20 ml of DMF, and the resulting solution was addeddropwise to a mixed liquid of 200 ml of acetone and 200 ml of ether,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 10 ml of methanol and 0.97ml of concentrated hydrochloric acid, and the solution was addeddropwise to a mixed liquid of 150 ml of acetone and 50 ml of ether,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain 651 mg of the desiredproduct.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.66(2H, S)    7.94(1H, dd, J1=8.9, J2=1.7Hz)    9.45(2H, S)           7.52-7.79(4H, m)    8.64(1H, d, J=1.7Hz)  7.04(1H, S)    8.32(1H, d, J=8.9Hz)  3.87-4.18(4H, m)    8.22(2H, d, J=8.6Hz)  3.45-3.67(2H, m)    8.09(1H, d, J=8.9Hz)    ______________________________________

Reference Example 8

Preparation of 6-cyano-1-carboxy-2-naphthol:

A solution prepared by dissolving 71 g of potassium hydroxide in 1.5liter of water was added to a solution prepared by dissolving 24.0 g of6-cyano-1-methoxycarbonyl-2-naphthol in 4.7 liters of methanol, followedby stirring at 50°-60° C. for 24 hours. After cooling, the reactionmixture was made to an acidic solution with addition of 10% hydrochloricacid. The precipitate was collected by filtration and washed with asmall amount of water to obtain 14.8 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    8.49(1H, d, J=1.7Hz) 8.44(1H, d, J=8.9Hz)    8.12(1H, d, J=8.9Hz)    7.82(1H, dd, J1=8.9, J2=1.7Hz)    7.36(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 32

Preparation of 6-amidino-1-carboxy-2-naphthol.methanesulfonate:

To 1.0 g of 6-cyano-1-carboxy-2-naphthol was added 100 ml of anhydrousmethanol, and dry hydrogen chloride gas was passed through the solutionunder cooling with ice and stirring to saturate the solution withhydrogen chloride gas. Thereafter, the resulting solution was furtherstirred for 72 hours under cooling with water. The solution was addeddropwise to 600 ml of anhydrous ether, followed by stirring for 1 hourunder cooling with ice. The resulting precipitate was collected byfiltration, and 50 ml of anhydrous methanol was added to the collectedprecipitate, and dry ammonia gas was passed through the solution undercooling with ice and stirring to saturate with ammonia gas and theresulting solution was further stirred for 72 hours under cooling withwater. The precipitate was collected by filtration and washed with amixed liquid of 20 ml of water and 20 ml of acetone. To this collectedprecipitate were added 10 ml of DMF and 0.8 ml of methanesulfonic acid,and the solution was added dropwise to 400 ml of ether, followed bystirring for 1 hour under cooling with ice. The precipitate wascollected by filtration and washed with a small amount of acetone toobtain 1.19 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.39(2H, S)    7.89(1H, dd, J1=9.2, J2=2.0Hz)    9.14(2H, S)          7.37(1H, d, J=8.9Hz)    8.39-8.62(2H, m)     2.44(3H, S)    8.15(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 33

Preparation of 6-amidino-1-carboxy-2-naphthyl 4-(4,5-dihydro-1H-imidzol-2-yl)amino!benzoate.dimethanesulfonate:

To 1.25 g of 6-amidino-1-carboxy-2-naphthol.methanesulfonate was added20 ml of anhydrous pyridine, and then thereto was added 1.0 g of 4-(4,5-dihydro-1H-imidzol-2-yl)amino!benzoic acid chloride.hydrochloride,followed by stirring for 2 hours under cooling with ice and 24 hoursunder cooling with water in a nitrogen gas stream. The precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue were added 60 ml of DMF and then 1 ml of methanesulfonicacid. The precipitate was filtered and the filtrate was concentratedunder reduced pressure. To the residue was added 15 ml of DMF, and thesolution was added dropwise to a mixed liquid of 100 ml of acetone and100 ml of ether, followed by stirring for 24 hours under cooling withice. Then, the precipitate was collected by filtration to obtain a crudeproduct. Then, the product was subjected to silica gel columnchromatography using methyl ethyl ketone-water-acetic acid (80:15:5) asan eluent, and the desired fractions were collected and the solvent wasdistilled off under reduced pressure. To the residue were added 10 ml ofDMF and 0.5 ml of methanesulfonic acid. The resulting solution was addeddropwise to 400 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain 715 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.26(1H, S)         8.19(2H, d, J=8.6Hz)    9.60(2H, S)    8.00(1H, dd, J1=8.9, J2=1.7Hz)    9.38(2H, S)          7.76(1H, d, J=8.9Hz)    8.79(2H, S)          7.51(2H, d, J=8.6Hz)    8.68(1H, d, J=1.7Hz) 3.75(4H, S)    8.35(1H, d, J=8.9Hz) 2.41(6H, S)    8.24(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 34

Preparation of 6-amidino-1-carboxy-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate:

To 930 mg of 6-amidino-1-carboxy-2-naphthol.methanesulfonate were added10 ml of anhydrous pyridine and then 667.5 mg of4-aminoiminomethylaminobenzoic acid chloride.hydrochloride, followed bystirring for 2 hours under cooling with ice and then 48 hours undercooling with water. The precipitate was collected by filtration andwashed with a small amount of pyridine. To the collected precipitatedwere added 20 ml of warm DMF and then 0.6 ml of methanesulfonic acid.The resulting solution was added dropwise to 600 ml of ether, followedby stirring for 1 hour under cooling with ice. The supernatant liquidwas decanted, and 20 ml of methanol was added to the residue. Thissolution was added dropwise to 450 ml of acetone, followed by stirringfor 15 minutes under cooling with ice. Then, the precipitate wascollected by filtration and washed with a small amount of acetone toobtain 869 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.27(1H, S)         8.18(2H, d, J=8.6Hz)    9.54(2H, S)    7.98(1H, dd, J1=8.9, J2=1.7Hz)    9.27(2H, S)          7.89(4H, S)    8.65(1H, d, J=1.7Hz) 7.75(1H, d, J=8.9Hz)    8.36(1H, d, J=9.2Hz) 7.47(2H, d, J=8.6Hz)    8.25(1H, d, J=9.2Hz) 2.44(6H, S)    ______________________________________

EXAMPLE 35

Preparation of 6-amidino-1-methoxycarbonyl-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoate.dihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.06 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.methanesulfonate, 1.2 gof 6-amidino-1-methoxycarbonyl-2-naphthol.methanesulfonate, 872 mg ofDCC and 43 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and 24 hours at room temperature. Furthermore, 436 mg of DCCand 7 ml of DMF were added, followed by stirring for 72 hours at roomtemperature. The precipitate was filtered and the filtrate wasconcentrated under reduced pressure. To the residue was added 15 ml ofDMF. The resulting solution was added dropwise to 200 ml of acetone,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 15 ml of methanol and 2.4 mlof concentrated hydrochloric acid. The resulting solution was addeddropwise to a mixed liquid of 100 ml of acetone and 200 ml of ether,followed by stirring for 1 hour under cooling with ice. Then, theprecipitate was collected by filtration to obtain 600.6 mg of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.71(1H, S)         8.13-8.31(3H, m)    9.76(2H, S)    8.04(1H, dd, J1=8.9, J2=1.7Hz)    9.54(2H, S)          7.78(1H, d, J=8.9Hz)    8.80(2H, S)          7.54(2H, d, J=8.6Hz)    8.75(1H, d, J=1.7Hz) 3.86(3H, S)    8.39(1H, d, J=8.9Hz) 3.74(4H, S)    ______________________________________

EXAMPLE 36

Preparation of 6-amidino-1-methoxycarbonyl-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate:

50 Milliliters of anhydrous pyridine was added to 1.9 g of4-aminoiminomethylaminobenzoic acid.hydro-chloride, 3.0 g of of6-amidino-1-methoxycarbonyl-2-naphthol.methanesulfonate, and 2.2 g ofDCC, followed by stirring for 2 hours under cooling with ice and 24hours at room temperature. The precipitate was collected by filtrationand washed with a small amount of pyridine. To the collected precipitatewas added 30 ml of water, followed by stirring for 1 hour. Insolublematter was filtered off and the filtrate was added dropwise to 100 ml ofsaturated aqueous sodium bicarbonate solution, followed by stirring for24 hours under cooling with ice. Then, the precipitate was collected byfiltration and washed with a small amount of water and acetone. To thecollected precipitate were added 15 ml of methanol and 2.2 ml ofmethanesulfonic acid. The resulting solution was added dropwise to 300ml of ether, followed by stirring for 24 hours under cooling with ice.Then, the precipitate was collected by filtration and washed with asmall amount of acetone to obtain 2.46 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.28(1H, S)    7.98(1H, dd, J1=8.9, J2=1.7Hz)    9.55(2H, S)          7.90(4H, S)    9.29(2H, S)          7.78(1H, d, J=8.9Hz)    8.67(1H, d, J=1.7Hz) 7.47(2H, d, J=8.6Hz)    8.41(1H, d, J=9.2Hz) 3.87(3H, S)    8.22(1H, d, J=9.2Hz) 2.42(6H, S)    8.17(2H, d, J=8.6Hz)    ______________________________________

EXAMPLE 37

Preparation of 6-amidino-1-carboxymethyl-2-naphthol.methanesulfonate:

To 12.4 g of 6-amidino-1-carbamoylmethyl-2-naphthol was added 370 g of25% hydrochloric acid, followed by stirring at 70° C. for 2.5 hours.After cooling with water, the precipitate was collected by filtrationand washed with 80 g of 15% hydrochloric acid. The collected precipitatewas added to a solution prepared by adding 200 ml of water to 10 g ofsodium bicarbonate, followed by stirring for 1 hour at room temperature,and the resulting precipitate was collected by filtration and washedwith water. This collected precipitate was added to a solution of 13 mlof methanesulfonic acid in 180 ml of water to dissolve the precipitateat 50° C. Furthermore, 1.0 g of active carbon was added to the solution,followed by stirring for 1 hour at room temperature. Thereafter,insoluble matter was filtered off and the filtrate was concentrated to90 ml under reduced pressure. This solution was stirred for 24 hoursunder cooling with water. Then, the precipitate was collected byfiltration and washed with a small amount of acetone and ether to obtain12.3 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    12.27(1H, br)        7.90(1H, d, J=8.9Hz)    10.41(1H, S)    7.77(1H, dd, J=8.9, J2=1.7Hz)    9.33(2H, S)          7.36(1H, d, J=8.9Hz)    9.04(2H, S)          4.00(2H, S)    8.41(1H, d, J=1.7Hz) 2.42(3H, S)    7.99(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 38

Preparation of6-amidino-1-methoxycarbonyl-methyl-2-naphthol.methanesulfonate:

To 6.0 g of 6-amidino-1-carboxymethyl-2-naphthol.methanesulfonate wasadded 200 ml of anhydrous methanol, and dry hydrogen chloride gas waspassed therethrough to saturate the solution with hydrogen chloride gasunder cooling with ice and stirring. Thereafter, the resulting solutionwas further stirred for 24 hours under cooling with water. The reactionmixture was concentrated under reduced pressure, and to the residue wasadded 300 ml of ether, followed by stirring for 24 hours under coolingwith ice. The resulting precipitate was collected by filtration, and 100ml of 0.5% dry ammonia gas-containing methanol was added to thecollected precipitate, followed by stirring for 1 hour under coolingwith ice. The precipitate was collected by filtration and washed with asmall amount of water and acetone. To the collected precipitate wereadded 100 ml of methanol and 2.02 ml of methanesulfonic acid, followedby stirring for 2 hours under cooling with ice. The solution wasconcentrated under reduced pressure, and to the residue was added 200 mlof acetone, followed by stirring for 1 hour under cooling with ice. Theresulting precipitate was collected by filtration to obtain 5.0 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.49(1H, S)    7.78(1H, dd, J1=8.9, J2=1.7Hz)    9.33(2H, S)          7.37(1H, d, J=8.9Hz)    9.05(2H, S)          4.10(2H, S)    8.41(1H, d, J=1.7Hz) 3.60(3H, S)    8.00(1H, d, J=8.9Hz) 2.42(3H, S)    7.92(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 39

Preparation of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoate.dimethanesulfonate:

60 Milliliters of 20% hydrous pyridine was added to 2.8 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.methanesulfonate, 3.0 gof 6-amidino-1-methoxycarbonylmethyl-2-naphthol.methanesulfonate, 4.19 gof DCC and 103.4 mg of DMAP, followed by stirring for 2 hours undercooling with ice and 48 hours at room temperature. The precipitate wasfiltered and the filtrate was concentrated under reduced pressure. Tothe residue was added 15 ml of DMF. The solution was added dropwise to amixed liquid of 500 ml of acetone and 300 ml of ether, followed bystirring for 24 hours under cooling with ice. Then, the precipitate wascollected by filtration to obtain a crude product. Then, the product wassubjected to silica gel column chromatography using methyl ethylketone-water-acetic acid (80:15:5) as an eluent, and the desiredfractions were collected and the solvent was distilled off under reducedpressure. To the residue were added 40 ml of methanol and 0.83 ml ofmethanesulfonic acid. The resulting solution was added dropwise to 400ml of acetone, followed by stirring for 30 minutes under cooling withice. Then, the precipitate was collected by filtration to obtain 1.4 gof the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.02(1H, S)    7.94(1H, dd, J1=8.9, J2=1.7Hz)    9.51(2H, S)          7.69(1H, d, J=8.9Hz)    9.26(2H, S)          7.50(2H, d, J=8.9Hz)    8.76(2H, S)          4.24(2H, S)    8.61(1H, d, J=1.7Hz) 3.76(4H, S)    8.37(1H, d, J=8.9Hz) 3.53(3H, S)    8.23(2H, d, J=8.9Hz) 2.41(6H, S)    8.19(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 40

Preparation of 6-amidino-1-carboxymethyl-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoate.dimethanesulfonate:

45 Milliliters of 10% aqueous methanesulfonic acid solution was added to500 mg of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoate.dimethanesulfonate,followed by stirring for 5 hours at 80° C. After leaving the mixture forcooling, 350 mg of active carbon was added to the reaction mixture,followed by stirring for 30 minutes at room temperature. Insolublematter was filtered off and the filtrate was concentrated under reducedpressure. To the residue was added a small amount of water. The solutionwas added dropwise to a mixed liquid of 150 ml of acetone and 50 ml ofether, followed by stirring for 1 hour under cooling with ice. Then, theprecipitate was collected by filtration and washed with a small amountof acetone to obtain 236.1 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.02(1H, brs)       8.16(1H, d, J=8.9Hz)    9.50(2H, S)    7.94(1H, dd, J1=8.9, J2=1.7Hz)    9.25(2H, S)          7.68(1H, d, J=8.9Hz)    8.77(2H, S)          7.50(2H, d, J=8.9Hz)    8.60(1H, d, J=1.7Hz) 4.12(2H, S)    8.35(1H, d, J=8.9Hz) 3.75(4H, S)    8.24(2H, d, J=8.9Hz) 2.43(6H, S)    ______________________________________

EXAMPLE 41

Preparation of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate:

170 Milliliters of anhydrous pyridine and 72 ml of DMF were added to 8.1g of 4-aminoiminomethylaminobenzoic acid.methanesulfonate, 10.0 g of6-amidino-1-methoxycarbonylmethyl-2-naphthol.methanesulfonate, 71.6 g ofDCC and 170 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and 24 hours at room temperature. The precipitate was filteredand washed with a small amount of DMF. The filtrate and the wash liquidwere combined and this was concentrated under reduced pressure. To theresidue was added 50 ml of DMF, and the resulting solution was addeddropwise to 700 ml of ether, followed by stirring for 24 hours undercooling with ice. The supernatant was decanted, and then to the residuewas added 200 ml of acetone, followed by stirring for 1 hour undercooling with ice. The precipitate was collected by filtration to obtaina crude product. To the collected precipitate was added 300 ml ofmethanol to dissolve the precipitate. To the solution was added 2 g ofactive carbon, followed by stirring for 30 minutes at room temperature.Insoluble matter was filtered off and the filtrate was concentratedunder reduced pressure. To the residue was added 100 ml of methanol todissolve the residue with heating. The resulting solution was addeddropwise to 300 ml of acetone, followed by stirring for 24 hours undercooling with ice. Then, the precipitate was collected by filtration toobtain 4.2 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.27(1H, S)         7.89(4H, S)    9.51(2H, S)          7.68(1H, d, J=8.9Hz)    9.23(2H, S)          7.48(2H, d, J=8.6Hz)    8.61(1H, d, J=1.7Hz) 4.23(2H, S)    8.36(1H, d, J=8.9Hz) 3.53(3H, S)    8.13-8.29(3H, m)     2.44(6H, S)    7.94(1H, dd, J1=8.9, J2=1.7Hz)    ______________________________________

EXAMPLE 42

Preparation of 6-amidino-1-carboxymethyl-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate:

30 Milliliters of 20% aqueous methanesulfonic acid solution was added to2.5 g of 6-amidino-1-methoxycarbonylmethyl-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate, followed by stirringfor 3 hours at 60° C. Then, 700 mg of active carbon was added to thereaction mixture, followed by stirring for 30 minutes at roomtemperature. Insoluble matter was filtered off and the filtrate wasconcentrated under reduced pressure. To the residue was added 30 ml ofwater to dissolve the residue. The solution was added dropwise to 150 mlof acetone, followed by stirring for 1 hour under cooling with ice.Then, the precipitate was collected by filtration and washed with asmall amount of acetone to obtain 580 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    12.53(1H, brs)       8.16(1H, d, J=8.9Hz)    10.26(1H, S)    7.92(1H, dd, J1=8.9, J2=1.7Hz)    9.50(2H, S)          7.89(4H, S)    9.22(2H, S)          7.67(1H, d, J=8.9Hz)    8.59(1H, d, J=1.7Hz) 7.47(2H, d, J=8.6Hz)    8.34(1H, d, J=8.9Hz) 4.12(2H, S)    8.23(2H, d, J=8.6Hz) 2.44(6H, S)    ______________________________________

EXAMPLE 43

Preparation of 6-amidino-1-(2-carbamoylethyl)-2-naphthyl4-aminoiminomethylaminobenzoate.methanesulfonate:

100 Milliliters of 20% hydrous pyridine was added to 3.16 g of4-aminoiminomethylaminobenzoic acid.methanesulfonate, 2.94 g of6-amidino-1-(2-carbamoylethyl)-2-naphthol and 4.54 g of DCC, followed bystirring for 2 hours under cooling with ice and 24 hours at roomtemperature. The precipitate was filtered and the filtrate wasconcentrated under reduced pressure. To the residue was added 20 ml ofDMF. The resulting solution was added dropwise to 500 ml of acetone,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Tothe collected precipitate was added 150 ml of methanol to dissolve theprecipitate. To the solution was added 3 g of active carbon, followed bystirring for 30 minutes at room temperature. Insoluble matter wasfiltered off and the filtrate was concentrated under reduced pressure.To the residue was added 30 ml of methanol to dissolve the residue withheating. The resulting solution was added dropwise to 400 ml of acetone,followed by stirring for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration to obtain 2.5 g of the desiredproduct.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.20-9.90(4H, br)  7.48(2H, d, J=8.6Hz)    8.62(1H, d, J=2.0Hz)                       7.41(1H, S)    8.37(1H, d, J=8.9Hz)                       6.84(1H, S)    8.28(2H, d, J=8.6Hz)                       3.12-3.37(2H, m)    7.72-8.17(6H, m)   2.28-2.47(5H, m)    7.61(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 44

Preparation of 6-amidino-1-(2-carboxyethyl)-2-naphthyl4-aminoiminomethylaminobenzoate.dihydrochloride:

300 Milliliters of 3.6% hydrochloric acid was added to 3.3 g of6-amidino-1-(2-carbamoylethyl)-2-naphthyl4-aminoiminomethylaminobenzoate.methanesulfonic acid hydrochloride,followed by stirring for 6 hours at 75°-80° C. Furthermore, the reactionmixture was stirried for 24 hours under cooling with ice. Then, theprecipitate was collected by filtration and washed with a small amountof 15% hydrochloric acid and acetone to obtain 1.58 g of the desiredproduct.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    12.30(1H, brs)     8.27(2H, d, J=8.6Hz)    10.78(1H, brs)     7.81-8.17(6H, m)    9.66(2H, S)        7.62(1H, d, J=8.9Hz)    9.43(2H, S)        7.49(2H, d, J=8.6Hz)    8.65(1H, d, J=1.7Hz)                       3.15-3.49(2H, m)    8.37(1H, d, J=8.9Hz)                       2.42-2.64(2H, m)    ______________________________________

Reference Example 9

Preparation of 1-formyl-6-cyano-2-naphthol:

65 milliliters of acetic acid was added to 20 g of 6-cyano-2-naphthol,3.6 g of paraformaldehyde and 16.6 g of hexamethylenetetramine, followedby stirring at 80° C. for 4 hours. Furthermore, to the reaction mixturewas added a solution comprising 53 ml of acetic acid, 10.5 ml of waterand 17.8 g of concentrated sulfuric acid at 60° C., followed by stirringat 80° C. for 4 hours. After cooling, 95 ml of water was added to theresulting solution, followed by stirring, and the precipitate wascollected by filtration and washed with 40 ml of warm water. To thecollected precipitate was added 350 ml of chloroform, followed byrefluxing for 1 hour. Thereafter, the precipitate was filtered and thefiltrate was concentrated under reduced pressure to obtain a crudeproduct. This product was subjected to silica gel column chromatographyusing chloroform as an eluent, and the desired fractions were collected,and the solvent was distilled off under reduced pressure. To the residuewas added 100 ml of n-hexane and the mixture was stirred for a while,and the precipitate was collected by filtration to obtain 11.2 g of thedesired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    13.33(1H, S)         8.03(1H, d, J=8.9Hz)    10.80(1H, S)    7.78(1H, dd, J1=8.9, J2=1.7Hz)    8.44(1H, d, J=8.9Hz) 7.28(1H, d, J=8.9Hz)    8.18(1H, d, J=1.7Hz)    ______________________________________

Reference Example 10

Preparation of 6-cyano-1-(2-ethoxycarbonylvinyl)-2-naphthol:

A solution prepared by dissolving 19.3 g of 1-formyl-6-cyano-2-naphtholand 42.1 g of ethoxycarbonylmethyltriphenylphosphonium bromide in 140 mlof DMF was added dropwise to a solution comprising 13.6 g of anhydrouspotassium carbonate and 250 ml of anhydrous methanol, followed bystirring for 3 hours under cooling with ice in a nitrogen stream and 24hours at room temperature. The precipitate was filtered, and 2.7 litersof water was added to the filtrate, followed by stirring for 2 hours.Then, the precipitate was collected by filtration and washed with 90 mlof methanol to obtain 12.6 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.38(1H, brs)       8.46(1H, d, J=1.7Hz)    8.09-8.30(2H, m)     7.98(1H, d, J=8.9Hz)    7.77(1H, dd, J1=8.9, J2=1.7Hz)    7.40(1H, d, J=8.9Hz) 6.84(1H, d, J=15.8Hz)    4.24(2H, q, J=7.3Hz) 1.31(3H, t, J=7.3Hz)    ______________________________________

Reference Example 11

Preparation of 6-cyano-1-(2-carbamoylvinyl)-2-naphthol:

2.0 Liters of 25% aqueous ammonia was added to 25.2 g of6-cyano-1-(2-ethoxycarbonylvinyl)-2-naphthol, followed by stirring at40°-45° C. for 32 hours. After cooling, the reaction mixture wasconcentrated to 300 ml under reduced pressure, and the residue wasstirred for 30 minutes under cooling with water. The precipitate wascollected by filtration and washed with a small amount of water andacetone to obtain 9.55 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    8.46(1H, d, J=1.7Hz) 8.22(1H, d, J=8.9Hz)    7.87-8.07(2H, m)    7.77(1H, dd, J1=8.9, J2=1.7Hz)    7.70(1H, S)          7.40(1H, d, J=8.9Hz)    7.16(1H, S)          6.94(1H, d, J=15.8Hz)    ______________________________________

EXAMPLE 45

Preparation of 6-amidino-1-(2-carbamoylvinyl)-2-naphthol.hydrochloride:

9.0 Grams of 6-cyano-1-(2-carbamoylvinyl)-2-naphthol was added to 750 mlof anhydrous methanol solution saturated with dry hydrogen chloride gas,followed by stirring for 72 hours under cooling with ice. Theprecipitate was collected by filtration and washed with small amounts ofether and acetone. This collected precipitate was added to 900 ml ofanhydrous methanol solution saturated with dry ammonia gas, followed bystirring for 120 hours at room temperature. The precipitate wascollected by filtration and washed with a small amount of methanol. Tothis collected precipitate was added 35 ml of DMF, and 15 g of 25%hydrochloric acid was added to the resulting solution, followed bystirring for 30 minutes under cooling with ice. Furthermore, to thissolution was added 200 ml of acetone, followed by stirring for 30minutes under cooling with ice. The precipitate was collected byfiltration and washed with small amounts of ether and acetone to obtain5.5 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    9.53(2H, S)          7.96(1H, d, J=8.9Hz)    9.30(2H, S)    7.90(1H, dd, J1=8.9, J2=1.7Hz)    8.50(1H, dd, J=1.7Hz)                         7.58(1H, d, J=8.9Hz)    8.26(1H, d, J=8.9Hz) 6.99(1H, d, J=15.8Hz)    8.02(1H, d, J=15.8Hz)    ______________________________________

EXAMPLE 46

Preparation of 6-amidino-1-(2-carbamoylvinyl)-2-naphthyl4-aminoiminomethylaminobenzoate.dihydrochloride:

90 Milliliters of 20% hydrous pyridine was added to 5.08 g of4-aminoiminomethylaminobenzoic acid.methanesulfonate, 4.5 g of6-amidino-1-(2-carbamoylvinyl)-2-naphthol.hydrochloride, 6.34 g of DCCand 80 mg of DMAP, followed by stirring for 2 hours under cooling withice and then 48 hours at room temperature. Then, the precipitate wascollected by filtration and washed twice with 160 ml of warm 20% hydrouspyridine. The above-obtained reaction filtrate and the warm hydrouspyridine wash liquid were combined and the resulting solution was addedto 1 liter of acetone, followed by stirring for 24 hours under coolingwith ice. The precipitate was collected by filtration and thereto wasadded 70 ml of warm DMF to dissolve the precipitate. Then, 0.5 g ofactive carbon was added, followed by stirring for 30 minutes at roomtemperature. Insoluble matter was filtered and 8.4 ml of concentratedhydrochloric acid was added to the filtrate. The resulting solution wasadded dropwise to 600 ml of acetone, followed by stirring for 24 hoursunder cooling with ice. Then, the precipitate was collected byfiltration to obtain 6.8 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.78(1H, S)       7.90-8.14(5H, m)    9.71(2H, S)        7.88(1H, S)    9.46(2H, S)        7.76(1H, d, J=15.8Hz)    8.70(1H, d, J=1.7Hz)                       7.70(1H, d, J=8.9Hz)    8.28(1H, d, J=8.9Hz)                       7.48(2H, d, J=8.6Hz)    8.23(2H, d, J=8.6Hz)                       7.28(1H, S)    8.22(1H, d, J=8.9Hz)                       6.65(1H, d, J=15.8Hz)    ______________________________________

Reference Example 12

Preparation of 6-cyano-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol:

To 28.4 g of 6-cyano-1-carboxy-2-naphthol were added 350 ml ofacetonitrile, 18 ml of triethylamine and 33.2 g ofdimethylcarbamoylmethyl bromide, followed by stirring for 24 hours at70° C. and further 24 hours at room temperature. The resultingprecipitate was collected by filtration and washed with water to obtain31.2 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.27(1H, S)         7.36(1H, d, J=8.9Hz)    8.52(1H, S)          5.23(2H, S)    8.37(1H, d, J=8.9Hz) 3.04(3H, S)    8.10(1H, d, J=8.9Hz) 2.95(3H, S)    7.80(1H, dd, J1=8.9, J2=1.7Hz)    ______________________________________

EXAMPLE 47

Preparation of6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol.hydrochloride:

600 Milliliters of anhydrous methanol was added to 29.8 g of6-cyano-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol, and dry hydrogenchloride gas was passed through the solution under cooling with ice andstirring to saturate the solution with hydrogen chloride gas, followedby further stirring for 24 hours under cooling with water. The reactionmixture was added dropwise to 3.0 liters of anhydrous methanol, followedby stirring for 1 hour under cooling with ice and the precipitate wascollected by filtration. This was added to a solution prepared bypassing dry ammonia gas through 240 ml of anhydrous methanol undercooling with ice and stirring to saturate the methanol with the gas,followed by stirring for 96 hours under cooling with water. Theprecipitate was collected by filtration and washed with 150 ml ofmethanol, 100 ml of water and 100 ml of acetone. To this collectedprecipitate was added 100 ml of a methanol solution saturated with dryhydrogen chloride gas, followed by stirring for 2 hours under coolingwith ice. The precipitate was collected by filtration and washed with asmall amount of diisopropyl ether to obtain a crude product. This wasdissolved in 1.2 liter of 50% hydrous methanol and 10 g of active carbonwas added thereto, followed by stirring for 1 hour at room temperature.Insoluble matter was filtered off and the filtrate was concentrated to200 ml under reduced pressure. Then, the precipitate was collected byfiltration and washed with small amounts of cold methanol and acetone toobtain 18.7 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.33(1H, S)    7.89(1H, dd, J=8.9, J2=1.7Hz)    9.53(2H, S)          7.44(1H, d, J=8.9Hz)    9.33(2H, S)          5.22(2H, S)    8.52(1H, d, J=1.7Hz) 3.04(3H, S)    8.43(1H, d, J=8.9Hz) 2.94(3H, S)    8.11(1H, d, J=8.9Hz)    ______________________________________

EXAMPLE 48

Preparation of 6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthyl4- (4,5-dihydro-1H-imidazol-2-yl)amino!benzoate.dihydrochloride:

15 Milliliters of anhydrous pyridine was added to 1.0 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!-benzoic acid.hydrochloride, 1.38 gof6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol.hydrochloride,1.28 g of DCC and 50.5 mg of DMAP, followed by stirring for 2 hoursunder cooling with ice and then 48 hours at room temperature. Then, theprecipitate was collected by filtration, and dissolved by adding thereto50 ml of warm DMF, 0.5 ml of 1N-hydrochloric acid and 2 ml of water,followed by stirring for 1 hour under cooling with ice. The precipitatewas filtered and the filtrate was concentrated under reduced pressure.To the residue was added 15 ml of DMF, and the solution was addeddropwise to a mixed liquid of 150 ml of acetone and 50 ml of ether,followed by stirring for 1 hour under cooling with ice. Then, theprecipitate was collected by filtration to obtain a crude product. Then,the product was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 5 ml of DMF and 0.7 ml ofconcentrated hydrochloric acid, and the solution was added dropwise to150 ml of acetone, followed by stirring for 24 hours under cooling withice. Then, the precipitate was collected by filtration to obtain 447.8mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.83(1H, brs)    8.07(1H, dd, J1=8.9, J2=1.7Hz)    9.81(2H, S)          7.79(1H, d, J=8.9Hz)    9.61(2H, S)          7.54(2H, d, J=8.6Hz)    8.85(2H, S)          5.12(2H, S)    8.84(1H, d, J=8.9Hz) 3.73(4H, S)    8.78(1H, d, J=1.7Hz) 2.97(3H, S)    8.38(1H, d, J=8.9Hz) 2.89(3H, S)    8.16(2H, d, J=8.6Hz)    ______________________________________

EXAMPLE 49

Preparation of 6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthyl4-aminoiminomethylaminobenzoate.dimethanesulfonate:

3 Milliliters of anhydrous pyridine was added to 418 mg of4-aminoiminomethylaminobenzoic acid.methanesulfonate, 500 mg of6-amidino-1-dimethylcarbamoylmethoxycarbonyl-2-naphthol.hydrochloride,400 mg of DCC and 18 mg of DMAP, followed by stirring for 2 hours undercooling with ice and then 24 hours at room temperature. Then, theprecipitate was collected by filtration and dissolved with addition of20 ml of warm DMF, followed by stirring for 1 hour under cooling withice. The precipitate was filtered and the filtrate was added dropwise to400 ml of ether, followed by stirring for 24 hours under cooling withice. The precipitate was collected by filtration and dissolved withaddition of 20 ml of water, and the solution was added dropwise to 100ml of aqueous sodium bicarbonate solution, followed by stirring for 2hours under cooling with ice. Then, the precipitate was collected byfiltration and washed with small amounts of water and acetone. This wasadded to a solution comprising 20 ml of DMF and 0.36 ml ofmethanesulfonic acid. The resulting solution was added dropwise to 450ml of acetone, followed by stirring for 24 hours under cooling with ice.Then, the precipitate was collected by filtration to obtain 312.5 mg ofthe desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.27(1H, S)         7.89(4H, S)    9.53(2H, S)          7.79(1H, d, J=8.9Hz)    9.27(2H, S)          7.46(2H, d, J=8.6Hz)    8.86(1H, d, J=8.9Hz) 5.11(2H, S)    8.66(1H, d, J=1.7Hz) 2.96(3H, S)    8.42(1H, d, J=8.9Hz) 2.89(3H, S)    8.17(2H, d, J=8.6Hz) 2.42(6H, S)    7.99(1H, dd, J1=8.9, J2=1.7Hz)    ______________________________________

EXAMPLE 50

Preparation of6-amidino-1-(2-ethoxycarbonylethyl)-2-naphthol.hydrochloride:

600 Milliliters of 3.6% hydrochloric acid was added to 3.6 g of6-amidino-1-(2-carbamoylethyl)-2-naphthol.hydrochloride, followed bystirring at 90° C. for 6 hours. The reaction mixture was concentratedunder reduced pressure, and to the residue was added 100 ml of ethanol,followed by stirring for 1 hour. Insoluble matter was filtered off, andthe filtrate was concentrated under reduced pressure. To the residue wasadded 200 ml of anhydrous methanol. Dry hydrogen chloride gas was passedthrough the solution under cooling with ice and stirring to saturate thesolution with the dry hydrogen chloride gas, followed by stirring for 24hours under cooling with water. A small amount of insoluble matter wasfiltered off and the filtrate was concentrated under reduced pressure.To the residue was added 60 ml of water to dissolve the residue. Theresulting solution was added dropwise to 140 ml of saturated aqueoussodium bicarbonate solution, followed by stirring for 30 minutes undercooling with ice. After the supernatant was decanted, a small amount ofwater was added to the residue and the supernatant was decanted. To theresidue were added 10 ml of ethanol and 5 ml of acetone and, further,4.3 ml of concentrated hydrochloric acid to dissolve the residue. Thissolution was added dropwise to 700 ml of ether, followed by stirring for2 hours under cooling with ice. The supernatant was decanted, and to theresidue were added 40 ml of acetone and 200 ml of ether, followed bystirring for 1 hour. Then, the precipitate was collected by filtrationto obtain 1.64 g of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    10.50(1H, S)       7.44(1H, d, J=8.9Hz)    9.46(2H, S)        4.05(2H, q, J=7.3Hz)    9.25(2H, S)        3.16-3.37(2H, m)    8.46(1H, d, J=1.7Hz)                       2.39-2.64(2H, m)    8.07(1H, d, J=8.9Hz)                       1.15(3H, t, J=7.3Hz)    7.74-7.92(2H, m)    ______________________________________

EXAMPLE 51

Preparation of 6-amidino-1-(2-ethoxycarbonylethyl)-2-naphthyl 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoate.dihydrochloride:

30 Milliliters of 20% hydrous pyridine was added to 1.12 g of 4-(4,5-dihydro-1H-imidazol-2-yl)amino!benzoic acid.hydrochloride, 1.5 g of6-amidino-1-(2-ethoxycarbonylethyl)-2-naphthol.hydrochloride, 1.44 g ofDCC and 56.7 mg of DMAP, followed by stirring for 2 hours under coolingwith ice and then 48 hours at room temperature. Furthermore, 1.44 g ofDCC, 5 ml of 20% hydrous pyridine and 10 ml of DMF were added, followedby stirring for 24 hours at room temperature. Then, the precipitate wasfiltered and the filtrate was concentrated rated under reduced pressure.To the residue was added 20 ml of DMF, and the resulting solution wasadded dropwise to 400 ml of ether, followed by stirring for 24 hoursunder cooling with ice. The supernatant was decanted to obtain a crudeproduct. This was subjected to silica gel column chromatography usingmethyl ethyl ketone-water-acetic acid (80:15:5) as an eluent, and thedesired fractions were collected and the solvent was distilled off underreduced pressure. To the residue were added 10 ml of ethanol and 1.55 mlof concentrated hydrochloric acid, followed by stirring for 1 hour undercooling with ice. Then, the precipitate was collected by filtration toobtain 307.9 mg of the desired product.

¹ H-NMR (DMSO-d₆) δ ppm:

    ______________________________________    11.71(1H, S)         8.09(1H, d, J=8.9Hz)    9.70(2H, S)    8.01(1H, dd, J1=8.9, J2=1.7Hz)    9.50(2H, S)          7.62(1H, d, J=8.9Hz)    8.79(2H, S)          7.55(2H, d, J=8.6Hz)    8.67(1H, d, J=1.7Hz) 3.98(2H, q, J=6.9Hz)    8.36(1H, d, J=8.9Hz) 3.74(4H, S)    8.25(2H, d, J=8.6Hz) 1.06(3H, t, J=6.9Hz)    ______________________________________

Formulation Example 1

    ______________________________________    The present compound   100    mg    Lactose                30     mg    Avicel                 30     mg    Carboxycellulose       20     mg    Succinic acid          18     mg    Magnesium stearate     2      mg    ______________________________________

The above components (200 mg in total) are filled into a capsule ortableted.

Formulation Example 2

    ______________________________________    The present compound   100    mg    Lactose                50     mg    Avicel                 20     mg    Carboxycellulose       20     mg    Succinic acid          8      mg    Magnesium stearate     2      mg    ______________________________________

The above components (200 mg in total) are filled into a capsule ortableted.

Formulation Example 3

    ______________________________________    The present compound     100    mg    Lactose                  45     mg    Corn starch              27     mg    Low-substitution hydroxypropylcellulose                             27     mg    Magnesium stearate       1      mg    ______________________________________

The above components (200 mg in total) are filled into a capsule ortableted.

Formulation Example 4

    ______________________________________    The present compound   0.2   g    Witepsol               1.1   g    ______________________________________

The above components were formulated into a suppository by aconventional method.

Effects of the Invention

The present compound which can be orally administered has fibrinolysispromoting action and exhibits excellent thrombolytic activity and,therefore, is effective for treatment of diseases caused by thrombus.That is, it can be used as medicines for general thrombosis andembolism, for example, medicines for treatment of thrombosis andembolism such as venous thrombosis, myocardial infarction, pulmonaryocclusion, cerebral embolism, slowly advancing cerebral thrombosis, andthrombosis and embolism caused by operation of blood vessels andextracorporeal circulation, and improvement of obstruction of bloodstream, improvement of various diseases caused by chronic arteryocclusion, and treatment of thrombosis and embolism caused by ischemiccerebral artery injuries.

It has been proved by the following experiments that the presentcompounds have fibrinolysis promoting action and exhibit excellentthrombus-resolving action and, therefore, are effective for treatment ofvarious diseases caused by thrombus.

(1) Preventive effect on death due to pulmonary thrombosis of mousemodels:

For experiment, ddy male mice after a fast of 6 hours were used and 10mg/kg of the present compound was orally administered. For positivecontrol group, was administered Sepimostat mesilate which exhibitsthrombolytic activity for human through oral administration. After lapseof 6 hours, 10 units/mouse of thrombin was administered to the micethrough caudal vein to cause thrombosis for the mice. After 16 hoursfrom thrombin-induction, mortality was checked and the preventive effecton death (survival rate) was indicated by the ratio to the survival rateof the positive control group. The results are shown in Table 1.

                  TABLE 1    ______________________________________                  Preventive effect    Compound      on death    ______________________________________    Example 1     1.16    Example 3     1.09    Example 5     1.00    Example 7     1.05    Example 11    1.12    Example 12    1.05    Example 15    1.05    Example 31    1.00    Example 39    1.19    Example 48    0.96    ______________________________________

The above results show that the present compounds have the effect equalto the control compound having excellent thrombus-resolving action.

(2) Test of determination of blood plasmin like activity using syntheticsubstrate:

For the test, SD male rats (8 weeks old) after fasted overnight wereused, and 100 mg/kg of the present compound was orally administered tothe rats, and blood was drawn, with time, from the descending aorta ascitrate-containing blood and subjected to centrifugation to obtainplasma. Water was orally administered to the rats of control group andplasma was similarly obtained.

To the plasma obtained were added 0.1M borate buffer solution (pH 8.5)and Boc-Val-Leu-Lys-MCA and incubation was conducted at 37° C. for 30minutes. Thereto was added 15% acetic acid to terminate the reaction,and thereafter, fluorescence intensity was measured to determine plasminlike activity to find that the present compound showed increase of bloodplasmin like activity. The results are shown in Table 2.

                  TABLE 2    ______________________________________                 Plasmin like activity    Compound     (nmol/min/ml)    ______________________________________    Example 1    0.37    Example 7    0.62    Example 17   0.62    Example 24   0.55    Example 26   0.60    Example 27   0.52    Example 39   0.58    Example 46   0.63    Water        0.07    ______________________________________

The above results clearly show that the present compounds exhibitthrombolytic activity.

(3) Test of measurement of plasminogen activator inhibitor (PAI-1)antigen quantity:

Measurement of PAI-1 antigen quantity was conducted using the plasmaobtained in the above Test (2).

Previously, 100 μl of a diluted 10 mM carbonate buffered solution ofmonoclonal antibody to PAI-1 was put in each well of a 96-wellmicro-titer plate and left to stand for 16 hours at 4° C., followed bywashing, four times, with 10 mM phosphate buffer solution containing0.1% Tween 20 and adding a standard solution and the plasma sample.After leaving for 2 hours at room temperature and washing again fourtimes, 100 μl of an enzyme-labelled PAI-1 polyclonal antibody was addedto carry out reaction at room temperature for 2 hours. After excessantibody was washed, 100 μl of citric acid buffer solution containing 10mg of o-phenylenediamine and 0.1% hydrogen peroxide was added, followedby leaving it for 30 minutes at 30° C. to cause color formation. Afterthe reaction was terminated by the addition of 50 μl of 2N sulfuricacid, absorbance at 405 nm was measured by a micro-plate reader todetermine the PAI-1 antigen quantity in the plasma sample. The resultsare shown in Table 3.

                  TABLE 3    ______________________________________                 PAI-1 antigen quantity    Compound     (ng/ml)    ______________________________________    Example 1    28.5    Water        54.2    ______________________________________

In the control mechanism of thrombolysis, most of t-PA released intoplasma is rapidly inhibited by PAI-1 which is the specific inhibitor andloses activity. Therefore, decrease of quantity of PAI-1 results inpromotion of thrombus-resolving action. In the group treated with thepresent compound, the blood PAI-1 antigen quantity was clearly reduced.

By the way, it is recognized that the toxicity of the present compoundsis very low and administration of them to human and mammals cause noproblem.

We claim:
 1. A compound represented by the formula (I) orpharmaceutically acceptable acid addition salts thereof: ##STR8##wherein R₁ represents (4,5-dihydro-1H-imidazol-2-yl)amino group,(4,5-dihydro-1,3-thiazol-2-yl)amino group, amidino group,morpholinomethyl group, nitro group, amino group, dimethylamino group,##STR9## R₃ represents hydrogen, methoxy group, hydroxyl group,acetylamino group, morpholino group, piperidino group, 1-pyrrolidinylgroup or dimethylamino group,m represents 0-4, R₄ represents hydrogen ormethyl group, R₂ represents NH₂ CO(CH₂)_(n) --, 2-(carbamoyl)vinyl groupor R₅ OOC(CH₂)_(n) --, R₅ represents dimethylcarbamoylmethyl group,hydrogen or lower alkyl group, and n represents 0-2.
 2. A compoundaccording to claim 1 which is represented by the formula (V) orphamaceutically acceptable acid addition salts thereof: ##STR10##wherein R₁ represents (4,5-dihydro-1H-imidazol-2-yl)amino group, R₂represents NH₂ CO(CH₂)_(n) --, andn represents 0-2.
 3. A pharmaceuticalformulation which contains the compound of claim 1 together with atleast one pharmaceutically acceptable carrier.
 4. A pharmaceuticalformulation according to claim 3 which is a fibrinolysis promoter.
 5. Acompound represented by the formula (II): ##STR11## wherein R₂represents NH₂ CO(CH₂)_(n) --, 2-(carbamoyl)vinyl group or R₅OOC(CH₂)_(n) --,R₅ represents dimethylcarbamoylmethyl group, hydrogen orlower alkyl group, and n represents 0-2, wherein n cannot equal 0 if R₅=CH₃.
 6. A pharmaceutical formulation which contains the compound ofclaim 2 together with at least one pharmaceutically acceptable carrier.7. A method for treating thrombotic conditions in humans and mammals,which comprises administering to a human or mammal in need thereof aneffective amount of the compound defined in claim
 1. 8. A method fortreating thrombotic conditions in humans and mammals, which comprisesadministering to a human or mammal in need thereof an effective amountof the compound defined in claim
 2. 9. A method for lysis of thrombus inhumans or mammals, which comprises administering to a human or mammal inneed thereof an effective amount of the compound defined in claim
 1. 10.A method for lysis of thrombus in humans or mammals, which comprisesadministering to a human or mammal in need thereof an effective amountof the compound defined in claim
 2. 11. A method of promotingfibrinolysis action in humans or mammals, which comprises administeringto a human or mammal in need thereof an effective amount of the compounddefined in claim
 1. 12. A method of promoting fibrinolysis action inhumans or mammals, which comprises administering to a human or mammal inneed thereof an effective amount of the compound defined in claim 2.